Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2(~ 3893
DESCRIPTION
BACKGROUND OF THE INVENTION
The present invention relates to novel compositions of matter and
novel processes for preparing these compositions of ma~ter. Moreover,
there are provided novel methods by which certain of these novel
compositions of matter are employed for pharmacologically useful
purposes. Further there are provided novel chemical intermediates for
preparing these compositions of matterO
The present invention is specifically concerned with novel ana-
logs of prostacyclin or PGI2. Specifically, the present invention is
concerned with analogs of carbacyclin modified at the C-5 or C-9
position, e.g., C-5 inter-phenylene analogs of carbacyclin, 5-fluoro
analogs of carbacyclin, 9~-alkyl analogs o~ carbacyclin, C-6a,9 tri-
cyclic (cyclopropyl) analogs of carbacyclin, and combinations thereof
as well as novel benzindene analogs thereof.
Prostacyclin is an endogenously produced compound in mammalian
species, being structuraily and biosynthetically related to the
prostaglandins (PG's). In particular, prostacyclin exhibits the
structure and carbon atom numbering of formula I when the C-5,6
positions are unsaturated. For convenience, prostacyciin is often
referred to simply as "PGI2". Carbacyclin, 6a-carba-PGI2, exhibits
the structure and carbon atom numbering indicated in formula II when
the C-5,6 positions are unsaturated. Likewise, for convenience, car-
bacyclin is referred to simply as "CBA2"~
A stable partially saturated derivative of PGI2 is PGI1 or5,6-dihydro-PGI2 when the C-5,6 positions are saturated, depicted with
carbon atom numbering in formula II when the C-5,6 positions are
saturated. The corresponding 5,6-dihydro-CBA? is CBAI, depicted in
formula II.
As is apparent from inspection of formulas I and II, prostacyclin
and carbacyclin may be trivially named as derivatives of PGF-type
compounds, e.g., PGF2~ of formula III. Accordingly, pros~acyclin is
trivially named 9-deoxy-6,9~-epoxy-(5Z)-5,6-didehydro-PGF1 and carba-
cyclin is named 9-deoxy-639~-methano-(5E)-5,6-didehydro-PGF1. For
description of prostacyclin and its structural identification, see
Johnson, et. alO, Prostaglandins 12:915 (1976).
For convenience, the novel prostacyclin or carbacyclin analogs
... ... . ..
Z ~ .
~ ~O~l7:1~
- ~ 3704/3803/3823/3833/3879/3893
--2--
will be referred to by the trivial, art-recognized system of nomen-
clature described by N.A. Nelson, J~ Med. Chem. 17:911 (1974) for
prostaglandins. Accordingly, all of the novel prostacyclin deriva-
tives herein will be named as 9-deoxy-PGF1-type compounds, PGI2 deri-
vatives~ or preferably as C8A1 or CBA2 derivatives.
In the formulas herein, broken line attachments to a ring indi-
cate substituents in the "alpha" ta) configuration, iOe., below the
plane of said ring. Heavy solid line attachments to a ring indicate
substituents in the "beta" (~) configuration, i~e., above the plane of
said ring. The use of wavy lines (~) herein will represent attachment
of substituents in the alpha or beta configuration or attached in a
mixture of alpha and beta configurations. Alternatively wavy lines
will represent either an E or Z geometric isomeric configuration or
the mixture thereof.
A side chain hydroxy at C-l5 in the formulas herein is in the S
or R configuration as determined by the Cahn-Ingold-Prelog sequence
rules, J. Chem. Ed.~41:16 (1964). See also Nature 212:38 (1966) for
discussion of the stereochemistry of the prostaglandins which dis-
cussion applies to the novel prostacyclin or carbacyclin analogs
herein. Molecules of prostacyclin and carbacyclin each have several
centers of asymmetry and therefore can exist in optically inactive
form or in either of two enantiomeric (optically active) forms, i.e.,
the dextrorotatory and laveorotatory forms. As drawn5 the formula
for PGI2 corresponds to that endogenously produced in the mammalian
species. In particular, refer to the stereochemical configuration at
C-8 (~), C-9 (~), C-ll (a) and C-12 (~) of endogenously produced
prostacyclin. The mirror image of the above formula for prostacyclin
represents the other enantiomer. The racemic form of prostacyclin
contains equal numbers of both enantiomeric molecules.
For convenience, reference to prostacyclin and carbacyclin will
refer to the optically active form thereof. Thus, with reference to
prostacyclin, reference is made to the form thereof with the same
absolute configuration as that obtained from the mammalian species.
The term "prostacyclin-type" product, as used herein, refers to
any cyclopentane derivative herein which is useful for at least one of
the same pharmacological purposes for which pros~acyclin is employedO
A formula as drawn herein which depicts a prostacyclin-type product or
an intermediate useful in the preparation thereof, represents that
2(~7 ~ 3704/3803/3~23/3833/3879/3893
particular stereoisomer of the prostacyclin-type produc~ which is of
the same relative stereochemical configuration as pros~acyclin ob-
tained from mammalian tissues or the particular stereoisomer of the
intermediate which is useful in preparing the above stereoisomer of
the prostacyclin type product.
The term "prostacyclin analog" or "carbacyclin analog" represents
that stereoisomer of a prostacyclin-type product which is of the same
relative stereochemical configuration as prostacyclin obtained from
mammalian tissues or a mixture comprising stereoisomer and the enan-
tiomers thereof. In particular, where a formula is used to depict aprostacyclin type produc~ herein, the term "prostacyclin analog" or
"carbacyclin analog" refers to the ccmpound of that formula or a mix-
ture comprising that compound and the enantiomer thereof.
PRIOR ART
Carbacyclin and closely related compounds are known in the art.
See Japanese Kokia 63,059 and 639060, also abstracted respectively as
Derwent Farmdoc CPI Numbers 48154B/26 and 48155B/26D See also ~ritish
published specifications 2,012,265 and German Offenlungsschrift
2,900,352, abstracted as Derwen~ Farmdoc CPI Number 54825B/30. See
also British published applications 2,0l7,699, 2,014,143 and
2,013,661.
The synthesis of carbacyclin and related compounds is also
reported in the chemical literature, as follows: Morton, D.R.~ et
al., J. Organic Chemistry, 44:2~80 (1979); Shibasaki, M., et al.
Tetrahedron Letters, 433-436 (1979); Kojima, K., et al.9 Tetrahedron
Letters, 3743-3746 (1g78); Nicolaou, KoC~ et al., J. Chem. Soc.,
Chemical Communications, 1067-1068 (1978); Sugie, A., et al., Tetra-
hedron Letters 2607-2610 (1979); Shibasaki, M., Chemistry Letters,
1299-1300 (l979), and Hayashi, M., Chem. Lett. 1437-40 (197g); and Li,
Tsung-tee, "A Facile Synthesis of 9(0)-Methano-prostacyclin", Abstract
No. 378, (Organic Chemistry), and P. A. Aristoff, 'iSynthesis of ~a-
Carbaprostacyclin I2", Abstract No. 236 ~Organic Chemistry) both at
Abstract of Papers (Part II) Second Conyress of ~he North American
Continent, San Francisco, California (Las Vegas, Nevada~, USA, 24-29
August 1980.
7-Oxo and 7-hydroxy-C~A2 compounds are apparently
disclosed in United States Patent 4~192~891D
19-Hydro~y-CBA2 compounds are also knownO CBA2
~ q~ 3704/3803/3823/3833/~879/3893
aromatic esters are disclosed in United States Patent 4,180,657.
11-Deoxy-~1- or ~ CBA2 compounds are described in Japanese Kokai
77/24~865, published 24 February 1979.
SUMMARY OF THE INVENTION
The present specification particularly provides:
(a) a carbacyclin intermediate of formula IV, V~ Vl, VII9 VIII,
or IX; and
(b) a carbacyclin analog of formula X or XI;
wherein g is 0, 1, 2, or 3;
wherein n is one or 2;
wherein L1 is a-R3:~-R4, a-R4:~-R3, or a mixture of ~-R3:B-R4 and
a-R4: ~-R3, wherein R3 and R4 are hydrogen, methyl, or fluoro, being
the same or different, with the proviso tha~ one of R3 and R4 is
fluoro only when the other is hydrogen or fluoro;
wherein M1 is a-OH:~-Rs or a-Rs:~-OH, wherein Rs is hydrogen or
methyl;
wherein M6 is ~-ORlo~-Rs or a-R5:~-OR1o, wherein R5 is hydrogen
or methyl and Rlo is an acid hydrolyzable protective group;
wherein R7 is
(1) -CmH2m-CH3, wherein m is an integer from one to 5,
inclusive,
(2) phenoxy optionally substituted by one9 two or three
chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (Cl-C3)alkoxy, with
the proviso that not more than two substituents are ottler than alkyl,
with the proviso that R7 is phenoxy or substituted phenoxy, only when
R3 and R4 are hydrogen or methyl, being the same or different,
(3) phenyl, ben2yl, phenylethyl, or phenylpropyl optionally
substituted on the aromatic ring by one, two or three chloro, fluoro,
trifluoromethyl, (Cl-C3)alkyl, or (C1-C3)alkoxy, with the proviso that
not more than two substituents are other than alkyl,
(4) cis-CH=CH-CH2-CH3,
(5) -(CH2)2-CH(OH) CH3, or
(6) -(CH2)3-CH=C(CH3)2;
wherein -C(L1)-R7 taken together is
(1) (C4-C7)cycloalkyl optionally substituted by one to 3
(C1-Cs) alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3-thienyl)ethoxy, or
'~ ~ 2
3704/3803/3823/3833/3879/3893
-5-
(4) 3-thienyloxymethyl;
wherein R8 is hydroxy, hydroxymethyl, or hydroge~;
wherein Rl5 is hydrogen or fluoro;
wherein R16 is hydrogen or Rl6 and Rl7 taken together are -CH2-
or Rl6 and R47 taken together form a second valence bond between C-6a
and C-9 or are -CH2-;
wherein R17 is as defined above or is
(1) hydrogen, or
(2 ) ~Cl-C4) alkyl;
10wherein Rl8 is hydrogen, hydroxy9 hydroxymethyl, -OR1o or
-CH20Rlo, wherein Rlo is an acid~hydrolyzable protective group,
wherein
(1) R20, R2l, R22, R23, and R24 are all hydrogen with R22
being either ~-hydrogen or ~-hydrogen,
15(2) R20 is hydrogen, R2l and R22 taken together form a
second valence bond betwen C-9 and C-6a, and R23 and R24 taken
together form a second valence bond between C-8 and C-9 or are both
hydrogen, or
(3) R22, R23, and R24 are all hydrogen, with R22 being
either a-hydrogen or ~-hydrogen9 and
(a) R20 and R21 taken together are oxo, or
(b) R20 is hydrogen and R2l is hydroxy, being -hydroxy
or ~-hydroxy;
wherein R27 is the same as R7 except that -(CH2)2-CH(OH)-CH3 is
t~ 25 -(CH2 ~CH(ORll)-CH3;
wherein R32 is hydrogen or R3l, wherein R3l is a hydroxyl
hydrogen replacing group;
wherein R33 is -CHO or -CH20R329 wherein R32 is as defined above;
wherein R~7 is as defined above or is
30(1) (Cl-C4)alkyl, or
(2) -CH20H;
wherein Xl is
COORl, wherein Rl is
(a) hydrogen,
35(b) (cl-cl2)alkyl~
(c) (C3-ClO)cycloalkyl,
(d) (C7-Cl2)aralkyl,
(e) phenyl, optionally substituted with one, 2 or 3
370~/3803/3823/3833/3879/3893
--6--
chloro or (Cl-C3)alkyl,
(f) phenyl subs~ituted in ~he para position by
( i ) -NH-CO-R2s,
(ii ) -CO-R26~
(iii) -O~CO-R54, or
(iv) -CH=N-NH-CO-NH2 wherein R2s is methyl 9
phenyl, acetamidophenyl, benzamidophenyl, or -NH2; R26 is methyl,
phenyl, -NH2, or methoxy; and R54 is phenyl or acetamidophenyl;
inclusive, or
(g) a pharmacologically acceptable cation;
(2) -CH20H,
(3) -COL4, wherein L4 i5
(a) amino of the formula -NR5lRs2~ wherein R5l and R52
are
(i) hydrogen,
(ii) (cl-cl2)alkyl,
(iii) (C3-ClO)cycloalkyl,
(iv) (C7-Cl2)aralkyl,
(v) phenyl, optionally substituted with one, 2 or
3 chloro, (Cl-C3)alkyl, hydroxy, carboxy, (C2-C5)alkoxycarbonyl, or
nitro,
(vi) (C2-C5)carboxyalkyl,
(vii) (C2-Cs)carbamoylalkyl,
(viii) (C2-Cs)cyanoalkyl~
(ix) ~C3-C6)acetylalkyl 7
(x) (C7-Cll)benzoalkyl, optionally substituted by
one, 2 or 3 chloro, tCl-C3)alkyl, hydroxy, (Cl-C3)alkoxy, carboxy,
(C2~C5)alkoxycarbonyl, or nitro,
(xi) pyridyl, optionally substituted by one, 2 or
3 chloro, (Cl-C3)alkyl, or (Cl-C3)alkoxy,
(xii) (C6-Cg)pyridylalkyl optionally substituted by
one, 2 or 3 chloro, (Cl-C3)alkyl, hydroxy, or (Cl-C3) ~ Y,
(xiii) (Cl-C4)hydroxyalkyl,
(xiv) (Cl-C4)dihydroxyalkyl,
(xv) (Cl-C4)trihydroxyalkyl,
with the further proviso that not more than one of R5l and R52 is
other than hydrogen or alkyl,
(b) cycloamino selected from the group consisting of
i2
370~/3803/3823/3833/3879/3893
--7--
pyrol i dino, pi peridi no, morpholino, piperazino, hexamethyl ene imi no,
pyrrolino,. or 3,4-didehydropiperidinyl optionally substituted by one
or 2 ~Cl-Cl2)alkyl of one to 12 carbon atoms, inclusive,
R~3 (c) carbonylamino of the formula -NR53CORsl, wherein
~3 is hydrogen or (Cl-C4)alkyl and R5l is other ~han hydrogen, but
otherwise as defined above,
(d) sulfonylamino o~ the formula -NRs3S02~5l, wherein
R2l and R23 are as defined in (c3,
(4) -CH2NL2L3, wherein L2 and L3 are hydrogQn or (Cl-C4~-
alkyl, being ~he same or different, or the pharmacologically accept~able acid addition salts thereof when Xl is -CH2NL2L3,
wherein Y1 is trans-CH=CH-, cis-CH~CH-, -CH2CH2-, or -C-C-;
wherein Zl is
(1) -CH2-(CH2)~-C(R2)29 wherein R2 is hydrogen or fluoro and
f is zero, one, 2, or 3,
(2) trans CH2-CH=CH-,
(3) -(Ph) (CH2)9-, wherein (Ph) is 1,2-, 1,3-, or
1,4-phenylene and 9 is zero, one, 2, or 3;
wherein Z4 iS -CH2- or -(CH2)f-CF2, wherein f is as defined
abovej
with the overall proviso that
(1) Rls, Rl6, and Rl7 are all hydrogen only when Zl is
-(Ph)-(CH2)g-, and
(2) Zl is -(Ph)-(CH2)9- only when Rls is hydrogen.
With regard to the divalent substitutents described above (e.g.,
Ll and Ml), these divalent radicals are defined as ~-Rj:3~Rj, wherein
Rj represents the substituent of the divalent moiety in the alpha
configuration with respect to the plane of the C-8 to C-12 cycl o-
pentane ring and Rj represents the substituent of the divalent moiety
in the beta configuration with respect to the plane oF the ring.
Accordingly, when Ml is defined as a-OH:~-R5, the hydroxy of the Ml
moiety is in the alpha con~iguration, i.eO~ as in PGI2 above, and the
R5 substituent is in the beta configuration.
The carbon atom content of various hydrocarbon-containing
moieties is indicated by a prefix designating the minimum and maximum
number of carbon atoms in the moiety, iDer, the prefix (Cj-Cj) indi-
cates a moiety of the integer "i" to the integer "j" carbon atoms,
inclusive. Thus (Gl-C3)alkyl refers to alkyl of one to 3 carbon
3704/3803/3823/3833/3879/38g3
atoms, inclusive, or methyl, ethyl, propyl, and isopropyl.
Certain novel prostacyclin analogs herein, i.e., formula X
compounds~ are all named as CBA1 or CBA2 compounds, respectively, by
virtue of the substitution of methylene for oxa in the heterocyclic
, 5 ring of prostacyclin~n~ thc su~s~ituti~n. CBA2 compounds are those
exhibiting the olefinic double bond at C-5,6, while CBA1 compounds are
those satura~ed at C-5,6. Formula XI compounds are named as PGE1 or
PGF1 derivatives as hereina~ter described.
Novel compounds wherein Z1 is (Ph)-(CH2)9 are designated
inter-o , inter-m-9 or inter-p-phenylene depending on whether the
attachment between C-5 and the -(CH2~9- moiety is ortho, meta, or
para, respectively.
For those compounds wherein g is zero, one, 2 or 3, the carba-
cyclin analogs so described are ~urther characterized as 2,3,4-
trinor-, 3,4-dinor-, or 4-nor, since in this event the X1-terminated
side chain contains (not including the phenylene) 2, 3, or 4 carbon
atoms, respectively, in place of the five carbon atoms contained in
PGI2. The missing carbon atom or atoms are considered to be at the
C-4 to C-2 positions such that the phenylene is connected to the C-5
and C-1 to C-3 positions. Accordingly these compounds are named as
1,5-, 2,5-, 3,5-, and 4,5-inter-phenylene-CBA compounds when g is
zero, one, 2, or 3, respectively.
Those CBA analogs wherein Z1 is -CH2-(CH2)f-CF2- are character-
ized as "2,2-difluoro-" compounds. For those compounds wherein f is
zero, 2, or 3, the carbacyclin analogs so described are further char-
acterized as 2-nor, 2a-homo, or 2a,2b-dihomo, since in this event the
X1-terminated side chain contains 4, 6, or 7 carbon atoms, respec-
tively, in place of the five carbon atoms contained in CBA2. The
missing carbon atom is considered to be at the C-2 position such that
the C 1 carbon atom is connected to the C-3 position. The additional
carbon atom or atoms are considered as though they were inserted
between the C-2 and C-3 positions. Accordingly these additional
carbon atoms are referred to as C-2a and C-2b, counting from the C-2
to the C-3 position.
Those CBA analogs wherein Z1 is trans CH2~CH=CH- are described as
"trans~2,3-didehydro-CBA" compounds.
Those novel compounds where n is 2 are further characterized as
7a-homo-CBA compounds by virtue of the cyclohexyl ring replacing the
_ ~L2~ 2 3704/3803/3823/3833/3879/38g3
heterocyclic ring of prostacyclinO
Further, the novel compounds are named as 9~-alkyl-CBA compounds
when R 17 is alkyl.
When R16 and R17 taken together are -CH2-(methylene), the novel
compounds so described are "6a~,3~-methano~CBA" compounds by virtue of
the methylene bridge between C-6a and C-9.
When R15 is fluoro, "5-fluoro-CBA" compounds are described.
The formula XI CBA analogs ~herein R20, R21, R22, R23, and R24
are all hydrogen with R22 being ~-hydrogen are characterized as
'~9-deoxy-2l~9a-methano-3-oxa-4~5~6-trinor-3~7~ 3l-inter-phenylene)-
PGF1" compounds. Corresponding compounds wherein R~2 is a-hydrogen
are character ked as "9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7
(1',3'-inter-phenylene)-PGF1" compounds. CBA analogs wherein R209
R23, and R24 are all hydrogen and R21 and R22 taken together form a
valence bond between C-9 and C-6a are characterized as "9-deoxo-2',9-
metheno-3-oxo-3,4,5-trinor-3,7-(1',3'-inter-phenylene)-PGF1" com-
pounds. CBA analogs wherein R20 is hydrogen and R21 and R22 taken
together form a second valence bond between C-9 and C-6a and R23 and
R24 taken together form a second valence bond between C-7 and C-8 are
characterized as "9-deoxo-2',9-metheno-3-oxa-3,4,5-trinor-3,7-(1',3'-
inter-phenylene)-7,8-didehydro-PGE1" compounds. The formula XI CBA
analogs wherein R22, R23, and R24 are all hydrogen and R20 and R21
taken together are oxo are characterized as "6a-oxo-9-deoxy-2',9a-
methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1" or
"6a-oxo-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-
phenylene)-PGF1" depending on whether R22 is a-hydrogen or ~-hydrogen,
respectively. Formula XI CBA analogs wherein R20, ~22~ R23. and ~24
are all hydrogen and R21 is a-hYdrOxY are characterized as "6a~-
hydroxy-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-~1',3'-inter-
phenylene)-PGF1" or "6aa-hydroxy-9-deoxy-2',9~-methano-3-oxa-4,5,6-
tr~nor-3,7-(1',3'-inter-phenylene)-PG~1" compounds depending on
whether R22 is a-hydrogen or ~-hydrogen, respectively. Finally,
formula XI ~ analogs wherein R20, R22, R23, and R24 are all hydrogen
and R21 is ~-hydroxy are characterized as "6a~-hydroxy-9-deoxy-2',9~-
methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1" or "6a~-
hydroxy-9-deoxy~2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-
phenylene) PGF1" compounds depending on whether R22 is a-hydrogen or
~-hydrogen, respectivelyO When Z4 is -(CH2)f-CF2 and f is zero, the
3704/3803/3~23/3833/3879/3893
-10-
formula XI CBA analogs are additionally characterized as "2,2-di-
fluoro" compounds. When f is one, 2, or 3, such compounds are addi-
tionally characterized as "2a-homo", "2a,2b-dihomo" or "2a,~b,2c-
trihomo" compoundsO
When R5 is methyl, the carbacyclin analogs are all named as
"15-methyl-CBA" compounds. Further9 except for compounds wherein Y1
is cis-CH=CH-, compounds wherein the M1 moiety contains an hydroxyl in
the beta configuration are additionally named as "15-epi-CBA" com-
pounds.
For the compounds wherein Yl is cis-CH=CH-, then compounds
wherein the ~1 moiety contains an hydroxyl in the alpha configuration
are named as "15-epi~C~A" compounds. For a description of this
convention of nomenclature for identifying C-15 epimers, see U.S.
Patent 4,016,184, issued 5 April 1977, particularly columns 24-27
thereof.
The novel carbacyclin analogs herein which contain -(CH2)2-,
cis-CH=CH-, or -C--C- as the Yl moiety, are accordingly referred to as
"13,14-dihydro"~ "cis-13", or "13914-didehydro" compounds, respec-
tively.
When R7 is straight chained -CmH2m-CH3, wherein m is as defined
above, the compounds so described are named as "19,2~-dinor",
"20-nor", "20-methyl" or "20-ethyl" compounds when m is one, 2, 4 or
5, respectively. When R7 is branched chain -CmH2m-~H3, then the
compounds so described are "17-, 18-, 19-, or 20-alkyl" or "17,17-,
17,18-, -17,19-, 17,20 , 18,18-, 18,19-, 1~,20-, 19,19-, or
19,20-dialkyl" compounds when m is 4 or 5 and the unbranched portion
of the chain is at least n-butyl, e.g., 17,20-dimethyl" compounds are
described when m is 5 (1-methylpentyl)~
When R7 is phenyl and neither R3 nor R4 is methyl, the compounds
so described are named as "16-phenyl-17,18,19,20-tetranor" compounds.
When R? is substituted phenyl, the corresponding compounds are named
as "16-(substituted phenyl)-17,18~19,20-tetranor" compounds. When one
and only one of R3 and R4 is methyl or both R3 and R4 are methyl~ then
the corresponding compounds wherein R7 is as defined in this paragraph
are named as "16-phenyl or 16-(substituted phenyl)-18,19,20-trinor"
compounds or "16-methyl-16-phenyl- or 16-(substituted phenylj-
18,19,20-trinor" compounds respectively.
When R7 is benzyl, the compounds so described are named as "17-
~L~ L~Yl~ 3704/3803/3823/3833/3&79/3893
phenyl-18,19,20-trinor" compounds. When R7 is substituted benzyl, the
corresponding compounds are named as "17-(substituted phenyl)-
18~19,20-trinor" compounds.
When R7 is phenylethyl, the compounds so described are named as
"18-phenyl~19,20-dinor" compounds~ When R7 is substituted phenyl-
ethyl, the corresponding compounds are named as "18-(substituted
phenyl)-19,20-dinor" compounds~
When R7 is phenylpropyl, the compounds so described are named as
"l9-phenyl-20-nor" compounds. When R7 is substituted phenylpropyl the
corresponding compounds are named as "19-(substituted phenyl)-20-nor"
compounds.
When R7 is phenoxy and neither R3 nor R4 is methyl, the compounds
so described are named dS "16-phenoxy 17,18,19,20-tetranor" compounds.
When R7 is substituted phenoxy, the corresponding compounds are named
as "16-(substituted phenoxy)-17,18,19,20-tetranor" compounds. When
one and only one of R3 and R4 is methyl or both R3 and R4 are me~hyl,
then the corresponding compounds wherein R7 is as defined in this
paragraph are named as "16-phenoxy or 16-(substituted phenoxy)-
18,19,20-trinor" compounds or "16-methyl-16-phenoxy- or 16-(substi-
tuted phenoxy)18,19,20-trinor" compounds, respectively.
When R7 is cis-CH=CH-CH2CH3, the compounds so described are named
as "cis-17,18-didehydro" compounds~
When R7 is -(CH2)2-CH(OH)-CH3, the compounds so described are
named as "19-hydroxy" compounds.
When R7 is -(CH2)3-CH=C(CH3)2, the compounds so described are
named as "20-isopropylidene" compounds.
When -C(Ll)-R7 is optionally substituted cycloalkyl, 2-(2-furyl)-
ethyl, 2-(3-thienyl)ethyl, or 3-thienyloxymethyl, the compounds so
described are respectively 15-cycloalkyl-16,17,18,19,20-pentanor com-
pounds, 17-(2-furyl)-18,19,20-trinor-CBA compounds, 17-(3-thienyl)
18~19,20-trinor compounds, or 16-(3-thienyl)oxy-17,18,19,20-tetranor
compo unds.
When at least one of R3 and R4 is not hydrogen then (except for
the 16-phenoxy or 16-phenyl compounds discussed above) there are
described the "16-methyl" (one and only one of R3 and R4 is methyl),
"16,16-dimethyl" (R3 and R4 are both methyl), "16~fluoro" (R3 or R~ is
fluoro), "16,16-dif1uoro" (R3 and R4 are both fluoro) compounds. For
those compounds wherein R3 and R4 are different, the prostaglandin
7 ~ 2 3704/3803/3823/3833/3879/3893
-12-
analogs so represented contain an asymmetric carbon atom at C-16.
Accordingly, two epimeric configurations are possible: "(16S)" and
"(16R)". Further, there is described by this invention the C-16
epimeric mixture: "(16RS)".
When X1 is -CH20H, the compounds SQ described are named as
"2-decarboxy-2-hydroxymethyl" compounds~
When Xl is -CH2NL2L3, the compounds so described are named as
"2-decarboxy-2-aminomethyl" or "2-(subs~ituted amino)methyl"
compounds~
When X1 is -COL4, the novel compounds herein are named as CBA-
type amides. Further, when X1 is -COORl, the novel compounds herein
are named as CBA-type esters and CBA-type salts.
Examples of phenyl esters substituted in the para position (i.e.,
Xl is -COOR1, Rl is p-substituted phenyl) include p-acetamidophenyl
ester, p-benzamidophenyl ester, p-(p-acetamidobenzamido)phenyl ester,
p-(p-benzamidobenzamido)phenyl ester, p-amidocarbo-nylaminophenyl
ester, p-acetylphenyl ester, p-benzylphenyl ester, p-amidocarbonyl-
phenyl ester, p-methoxycarbonylphenyl estPr, p-benzoyloxyphenyl ester,
p-(p-acetamidobenzoyloxy)phenyl ester, and p-hydroxybenzaldehyde
semicarbazone ester.
Examples of novel amides herein (i.e., Xl is -COL4) include the
following:
(1) Amides within the scope of alkylamino groups of the formula-
NR5lR52 are methylamide, ethylamide, n-propylamide 9 n-butylamide, n-
pentylamide, n hexylamide, n-heptylamide, n-octylamide, n-nonylamide,
n-decylamide, n-undecylamide, and n-dodecylamide, and isomeric forms
thereof. Further examples are dimethylamide, diethylamide, di-n-
propylamide, di-n-butylamide, methylethylamide, methylpropylamide,
methylbutylamide, ethylpropylamide, ethylbutylamide, and propylbutyl-
amide. Amides within the scope of cycloalkylamino are cyclopropyl-
~mide, cyclobutylamide, cyclopentylamide, 2,3-dimethylcyclopentyl-
amide, 2,2-dimethylcyclopentylamide, 2-methylcyclopentylamide, 3-tert-
butylcyclopentyl amide, cyclohexylamide, 4-tert-butylcyclohexylamide,
3-isopropylcyclohexylamide, 2,2-dimethylcyclohexylamide, cycloheptyl-
amide, cyclooctylamide, cyclononylamide, cyclodecylamide, N me~hyl-N-
cyclobu~ylamide, N-methyl-N-cyclopentylamide, N-methyl-N-cyclohexyl-
amide, N-ethyl-N-cyclopentylamide, and N-ethyl-Ncyclohexylamide.
Amides within the scope oi aralkylamino are benzylamide~ 2-phenyl-
~L~2Q~ 2 3704/3803/3823/3833/3879/38g3-13-
ethylamide, and N-methyl-N benzyl-amide~ Amides within the scope o~
substituted phenylamide are p-chloroanilide, m~chloroanilide, 2,4-
dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide, p-nitro-
anilide, p-methoxyanilide, 3,4-dimethoxyanilide, 3,4,5-trimethoxy-
S anilide, p-hy~roxymethyl~nilide, p-methylanilide, m-methyl anilide, p-ethylanilide, t-butylanilide, p-carboxyanilide, p-methoxycarbonyl
anilide, p-carboxyanilide and o-hydroxyanilide. Amides within the
scope of carboxyalkylamino are carboxyethylamide, carboxypropy1amide
and carboxymethylamide, carbo~ybutylamide. Amides within the scope of
carbamoylalkylamino are carbamoylmethylamide, carbamoylethylamide,
carbamoylpropylamide, and carbamoylbutylamide. Amides with;n the
scope o~ cyanoalkylamino are cyanomethylamide, cyanoethylamide, cyano-
propylamide, and cyanobutylamide. Amides within the scope of acetyl-
alkylamino are acetylmethylamide, acetylethylamide, acetylpropylamide,
and acetylbutylamide. Amides within the scope of benzoylalkylamino
are benzoylmethylamide, benzoylethylamide9 benzoylpropylamide, and
benzoylbutylamide. Amides within the scope of substituted benzoyl-
alkylamino are p-chlorobenzoylmethylamide, m-chlorobenzoylmethylamide,
2,4-dichlorobenzoylmethylamide, 2,4,6-trichlorobenzoylmethylamide,
m-nitrobenzoylmethy.lamide, p-nitrobenzoylmethylamide, p-methoxy-
benzoylmethylamide, 2,4-dimethoxy benzoylmethylamide, 3,4,5-tri-
methoxybenzoylmethylamide, p- hydroxymethylbenzoylmethylamide, p-
methylbenzoylmethylamide, m-methylbenzoylmethylamide, p-ethylbenzoyl-
methylamide, t-butylbenzoylmethylamide, p-carboxybenzoylmethylamide,
m-methoxycarbonylbenzoylmethylamide, o-carboxybenzoylmethylamide,
o-hydroxybenzoylmethylamide, p-chlorobenzoy1ethylamide, m-chloro-
benzoylethylamide, 2,4-dichlorobenzoylethylamide, 2,4,6-trichloro-
benzoylethylamide, m-nitrobenzoylethylamide, p nitrobenzoylethylamide,
p-methoxybenzoylethylamide, p-methoxybenzoylethylamide, 2,4-dimethoxy-
benzoyle~hylamide, 3,4,5trimethoxybenzoylethylamide, p-hydroxymethyl-
be~zoylethylamide, p-methylbenzoylethylamide, m-methylbenzoylethyl-
amide, p-ethylbenzoylethylamide9 t-butylbenzoylethylamide, p-carboxy-
benzoylethylamide, m-methoxycarbonylhenzoylethylamide9 o-carboxy-
benzoylethylamide, o-hydroxybenzoylethylamide, p-chlorobenzoylpropy1-
amide, m-chlorobenzoylpropylamide, 2,4-dichlorobenzoylpropylamide,
2,4,6-~richlorobenzoylpropylamide, m nitrobenzoylpropylamide,
p-nitrobenzoylpropylamide9 p-methoxybenzoylpropylamide, 2,4-dimeth-
oxybenzoylpropylamide9 3,49~-trimethoxybenzoylpropylamide, p-
L'7~
3704/3803/3823/3833/3879/389314-
hydroxymethyl benzoyl propyl amide~ p-methyl benzoyl propylamide, m-methyl-
benzoyl propyl amide, p-ethyl benzoyl propyl amide, t-butylben 70yl propyl-
amide, p-carboxybenzoyl propyl amide9 m-methoxycarbonyl benzoyl propyl-
amide, o-carboxybenzoylpropylamide, o-hydroxybenzoylpropylamide,
5 p-chlorobenzoylbutylamide, m-chlorobenzoylbutylamide, 274-dichloro-
benzoylbutylamide, 2,4,6-trichlorobenzoylbutylamide9 m-nitrobenzoyl-
methyl amide, p-nitrobenzoyl butyl amide, p-methoxybenzoyl butyl amide,
294-dimethoxybenzoylbutyl-amide, 3,~,5-trimethoxybenzoylbutylamide,
p-hydroxymethyl benzoyl butyl-amide, p-methyl benzoyl butyamide, m-methyl-
10 benzoylbutylamide, p-ethyl-benzoylbutya7mide, m-methylbenzoylbutyl-
amide, p-ethylbenzoyl hutyl-amide, t-butyl benzoyl butylamide, p-carboxy-
ben~oylbutylamide, m-methoxycarbonylbenzoylbutylamide, o-carboxyben-
zoylbutylamide, o-hydroxybenzoylmethylamide. Amides within the scope
of pyridylamino are a-pyridylamide, ~-pyridylamide, and Y-pyridyl-
15 amide. Amides within the scope of substituted pyridylamino are4-methyl-a-pyridyl amide, 4-methyl-~-pyridyl amide, 4-chl oro-a-
pyridylamide, and 4-chloro-~-pyridylamide. Amides within the scope of
pyridylalkylamino are a-pyridylmethylamide, ~-pyridylmethylamide,
y-pyridylmethyl amide, ~-pyridyl ethyl amide, ~-pyridyl ethyl amide,
20 y-pyridyl ethyl amide, ~-pyridyl propyl amide, ~-pyridyl propyl an~ide,
y-pyridyl propyl amide, a-pyridyl butyl amide, ~-pyridyl butyl amide, and
y-pyridylbutyl amide. Amidês within the scope of substituted pyridyl-
alkylamido are 4-methyl-a-pyridylmethylamide, 4-methyl-~-pyridyl-
methylamide, 4-chloro-~-pyridylmethylamide, 4-chloro-~-pyridylmethy7-
25 amide, 4-methyl-c-pyridyl propyl amide, 4-methyl-~-pyridyl propyl amide,
4-chloro-a-pyridyl propyl amide, 4-chloro-~-pyridyl propyl amide, ~-
methyl-a-pyridylbutylamide9 4-methyl-~-pyridyl butyl amide, 4-chl oro-
a-pyridylbutylamide~ 4-chloro-~ pyridylbutylamide, 4-chloro-y-
pyridylbutyl-amide. Amides within the scope o-f hydroxyalkylamino are
30 hydroxymethylamide, g-hydroxyethylamide, ~-hydroxypropylamide,
y-hydroxypropyl amide9 l-(hydroxymethyl)ethyl-amide, l-(hydroxymethyl)-
propyl amide, (2-hydroxymethyl) propyl amide, and c~,a~-dimethyl-hydroxy-
ethylamide. Amides within the scope of dihydroxyalky7amino are dihy-
droxymethyl amide 9 ~ ~ y-di hydroxypropyl amide, l-(hydroxymethyl )2 -
35 hydroxymethylamide, ~,y-dihydroxybutylamlde, ~a~-dihydroxybutyl-amide,
y,~-dihydroxybutylamide, and l,1-bis(hydroxymethyl)ethylamide. Amides
within the scope of trihydroxyalkylamino are ~ris(hydroxy-methyl)-
methyl amide and 1,3-dihydroxy-2-hydroxymethyl propyl amide.
~ ~?~
.~. ~ol~
3704/3803/3823/3833/3879/3893
-15-
(2) Amides within ~he scope of cycloamino group5 described above
are pyrrolidyl amide, pi peridyl amide, morpho7inyl amide, hexamethyl ene-
iminylamide, piperazinylamide, pyrro1inylamide, and 394-didehydro-
pi peridinyl amide.
(3) Amides within the scope of carbonylamino of the formula
-NRs3COR51 are methylcarbonylamide, ethylcarbonylamide, phenylcar-
bonyl amide, and benzylcarbonyl amide.
(4) Amides within the scope of sulfonylamino of the fornlula
-NRs3SO2R5l are methyl sul fonyl amide, ethyl sufonyl amide, phenyl sul-
10 fonyl amide, p-tolylsul fonyl amide, benzyl sul fonyl amide~
Examples of alkyl of one to 12 carbon atoms, inclusive, are
methyl, ethyl, propyl g butyl, pentyl, hexyl, heptyl, octyl, nonyl,
decyl, undecyl, dodecyl, isomeric forms thereof.
Examples of (C3-ClO)cycloalkyl which includes alkyl-substituted
15 cycl oal kyl, are cycl opropyl, 2-methyl cycl o-
propyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclo-
propyl, cyclobutyl, 2-methylcyclobutyl 9 3-propylcyclobutyl, 2,3,4-tri-
ethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclo-
pentyl 3 3-tert-butyl cycl opentyl, cycl ohexyl, 4-tert-butyl cycl ohexyl,
20 3-isopropylcyclohexyl, 292-dimethylcyclohexyl, cycloheptyl, cyclo-
octyl, cycl ononyl, and cycl odecyl.
Examples of (C7-Cl2)aralkyl are benzyl, 2-phenylethyl,
1- phenyl ethyl, 2- phenyl propyl, 4- phenyl butyl, 3- phenyl butyl,
2-(1-naphthylethyl), and 1-(2-naphthylmethyl).
Examples of phenyl substituted by one to 3 chloro or alkyl of one
to 4 carbon atoms, inclsive, are p-chlorophenyl, m chlorophenyl, 2,4-
dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-
ethyl phenyl, p-tert~butyl phenyl, 2,5-dimethyl phenyl, 4-chl oro-2-
methyl phenyl, and 2,4-dichloro-3-methyl phenyl.
Examples of (C5-C7)cycloalkyl optionally substitutecl by (Cl-C4)-
alkyl dre cyclobutyl, 1- propylcycl obutyl, 1-butylcyclobutyl, 1-pentyl-
cyclobutyl, 2-methylcycl obutyl, 2-propylcycl obutyl 3 3-ethylcycl obutyl,
3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-di~
methyl cycl opentyl, 3-ethylcycl opentyl, 3-propyl cycl opentyl, 3~butyl-
35 cyclopentyl, 3-tert-butylcyclopentyl, 1-methyl-3 propylcycl opentyl,
2-methyl-3-propyl cycl opentyl, 2-methyl-4-propylcycl opentyl, cycl o-
hexyl, 3-ethylcycl ohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl,
4-ethylcycl ohexyl, 4-propylcycl ohexyl, 4-butylcycl ohexyl, 4-tert-
7 ~ 3704/3803/3823/3833/3879/3893
-16-
butylcyclohexyl~ 2,6-dimethylcyclohexyl, 2,2-dimethylcyclohexyl,
2,6-dimethyl-4-propylcyclohexyl, and cycloheptyl,
Examples of substituted phenoxy, phenylmethyl~ phenylethyl, or
phenylpropyl of the R7 moiety are (0-3 m-, or p-)tolyl, (o-, m-, or
p-)ethylphenyl, ~-ethyl-o ~olyl, 5-ethyl-m-tolyl, (o 3 m-, or p-)-
propylphenyl, 2-propyl-(m- or p-)tolyl, 4-isopropyl-2,6-xylyl, 3-
propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5 )trimethyl-
phenyl, (o-, m-, or p-)fluorophenyl, 2-fluoro-(m- or p-)tolyl, 4-
fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-9 or 3,5-)difluorophenylg
(o-,m-, or p-)chlorophenyl, 2-chloro-p to7yl, (3-, 4-, 5-, or 6-)
chloro-o-tolylg 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl,
4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichloro-
phenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-~luorophenyl, (o-,
m-, or p-)tri~luoromethylphenyl, (o-, m-, or p-)methoxyphenyl, (o-,
m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxyphenyl, 2,4-
dichloro-(4- or 6-)methylphenyl, (o-, m-, or p-)tolyloxyg (o-, m-, or
p-)ethylphenyloxy, 4-ethyl-o-tolyloxy, 5-ethyl-m-tolyloxy, (o-, m-, or
p-)propylphenoxy, 2-propyl-(m- or p-)tolyloxy, 4-isopropyl-2,6-xylyl-
oxy, 3-propyl-4-ethylphenyloxy, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)-
trimethylphenoxy, (o-, m-, or p-)fluorophenoxy, 2-fluoro-(m- or p-)-
tolyloxy, 4-fluoro-2,5-xylyloxy, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)-
difluorophenoxy, (o-, m-, or p-)-chlorophenoxy, 2-chloro-p tolyloxy,
(3, 4, 5, or 6-)chloro-o-tolyloxy, 4-chloro-2-propylphenoxy, 2-iso-
propyl-4-chlorophenoxy, 4-chloro-3,5-xylyloxy, (2,3-, 2,4-, 2,5-,
2,6-, 3,4-, or 3,5-)dichlorophenyloxy, 4-chloro-3-fluorophenoxy, (3-
or 4-)chloro-2-fluorophenoxy, (o-, m-, or p-)trifluoromethylphenoxy,
(o~-, m-, or p-)methoxyphenoxy, (o-, m-, or p-)ethoxyphenoxy, (4- or
5-)chloro-2-methoxyphenoxy, 2,4-dichloro-(5- or 6-)rnethylphenoxy, (o-,
m-, or p-)tolylmethyl, (o-, m-, or p-)ethylphenyl methyl, 4-ethyl-o-
tolylmethyl, 5-ethyl-m-tolylmethyl, (o-, m-, or p-)propylphenylmethyl,
2-propyl-(m- or p-)tolylmethyl, 4-isopropyl-2,6-xylylme~hyl, 3-
propyl-4-ethylphenylmethyl, (2,3,4-, 2,3,5-~ 293,6-, or 2,4,5-)tri-
methylphenylmethyl, (o-, m-, or p-)fluorophenylmethyl, 2~fluoro-(m- or
p-)tolylmethyl, 4-~luoro-2,5-xylylmethyl 9 (2,4-, 2,5-, 2,6-, 3,4-, or
3,5-)difluorophenyl, (o-, m-, or p-)chlorophenylmethyl, 2-~hloro-p-
tolylmethyl, (3, 4, 5, or 6-)chloro-o-tolylmethyl, 4-chloro-2-propyl-
phenylmethyl, 2-isopropyl-4-chlorophenylmethyl, 4-chloro-3,5-xylyl-
methyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5 )dichlorophenylmethyl,
2~ 7 1~
` 3704/3803~3823/3833/3879/3893
-17-
4-chloro-3-fluorophenylmethyl, (3- or 4-)chloro-2-fluorophenylmethyl,
(o-, m-, or p-)trifluoromethylphenylmethyl~ (o-, m-, or p-)methoxy-
phenylmethyl, (o-, m-, or p-)ethoxyphenylmethyl, (4- or 5-)chloro-
2-methoxyphenylmethyl, and 2,4-dichloro-(4- or 6-)methoxyphenylmethyl.
The novel CBA analogs disclosed herein produce certain
prostacyclin-like pharmacological responses.
Accordingly, the novel ~ormula X and XI CBA ana10gs are used as
agents in the study, prevention, control, and treatment o~ diseases,
and other undesirable physiological conditions, in mammals~
particularly humans, valuable domestic animals, pets, zoological
specimens, and laboratory animals (e.g., mice, rats, rabbits and
monkeys)O In particular~ these compounds have useful application as
antithrombotic agents, anti-ulcer agents, and anti-asthma agents, as
indicated below.
(a) Platelet Aggregation Inhibition
These novel CBA analogs disclosed herein are useful whenever it
is desired to inhibit platelet aggregation, to reduce the adhesive
character of platelets, or to remove or prevent the formation of
thrombi in mammals9 including man. For example, these compounds are
useful in the treatment and prevention of myocardial infarcts, to
treat and prevent post-operative thrombosis, to promote patency of
vascular grafts following surgery, to treat peripheral vascular
diseases, and to treat conditions such as atherosclerosis, arterio-
sclerosis, blood clotting defects due to lipemia, and other clinical
conditions in which the underlying etiology is associated with 1ipid
imbalance or hyperlipidemia. Other in vivo applications include
geriatric patients to prevent cerebral ischemic attacks and long term
prophylaxis following myocardial infarcts and strokesO For these
purposes, these compounds are administered systemically, e.g.,
intravenously, subcutaneouslyl intramuscularly, and in the form of
sterile implants ~or prolonged action. For rapid response, especially
in emergency situations, the intravenous route of administration is
preferred. Doses in the range about 0.01 to about 10 mg per kg of
body weight per day are used, the exact dose depending on the age,
weight, and condition of the patient or animal, and on the frequency
and route of administration.
The preferred dosage form for these compounds is oral, although
other non-parenteral routes (eOg., buccal, rectal, sublingual) are
~2Q~'71Z
~~` 3704/3803/3~23/3~33/3879/3~93
-18-
- likewise employed in preference ~o parenteral routes. Oral dosage
forms are conventionally ~ormulated (tablets, capsules, et cetera) and
administered 2-4 times daily. Doses in the range of about 0005 to 100
mg per kg of body weight per day are effective.
The addition of these compounds to whole blood provides in vitro
applications such as storage of whole blood to be used in heart-lung
machines. Additionally whole blood containing these compounds can be
circulated through organs, e.g., heart and kidneys, which have been
removed from a donor prior to transplant. They are also useful in
preparing platelet rich concentrates for use in treating thrombo-
cytopenia, chemotherapy, and radiation therapyO In vitro applications
utilize a dose of 0~001-1.0 ~9 per ml of whole blood. For treatment
of peripheral vascular diseases, see U.S. Patent 4,103,026.
(b) Gastric Secretion Reduction
These novel CBA analogs disclosed herein are also useful in mam-
mals, including man and certain useful animals, e.g., dogs and pigs,
to reduce and control gastric secretion, thereby to reduce or avoid
gastrointestinal ulcer formation, and accelerate the healing of such
ulcers already present in the gastrointestinal tract. For this pur-
pose, these compounds are injected or infused intravenously, subcuta-
neously, or intramuscularly in an infusion dose range about 0.1 ~9 to
about 20 ~g per kg of body weight per minute, or in a total daily dose
by injection or infusion in the range about 0.01 to about 10 mg per kg
of body weight per day, the exact dose depending on the age, weight,
and condition of the patient or animal, and on the frequency and route
of administration.
Preferably, however, these novel compounds are administered
orally or by other non-parenteral routes~ As employed orally, one to
6 administrations daily in a dosage range of about 1.0 to 100 mg per
kg of body weight per day is employed. Once healing of the ulcers has
been accomplished the maintenance dosage required to prevent recur-
rence is adjusted downward so long as the patient or animals remains
asymptomatic.
(c) NOSAC-Induced Lesion Inhibition
These novel CBA analogs disclosed herein are also useful in
reducing the undesirable gastrointestinal effects resulking from
systemic administration of anti-inflammatory prostaglandin synthetase
inhibitors, and are useful ~or that purpose by concomitant adminis-
12~?~'712
3704/3803/3823/3833/3879/3893
-19-
tration of the prostaglandin derivative and the anti-inflammatory
prostaglandin synthetase inhibitor. See Partridge, et al., IJ.S.
Patent No. 3,781,429, fon a disclosure that the ulcerogenic effect
induced by certain non-steroidal anti-inflammatory agents in rats is
inhibitPd by concomitant oral administration of certain prostaglan-
dins. Accordingly these novel CBA analogs herein are useful, for
example, in reducing the undesirable gastrointestinal effects result-
ing from systemic administration of indomethacin, phenylbutazone, and
aspirin~ These are substances specifically mentioned in Partridge, et
al. as non-steroidal, anti-inflammatory agents. These are also known
to be prostaglandin synthetase inhibitorsc
The anti-inflammatory synthetase inhibitor 9 for example, indome-
thacin, aspirin, or phenylbutazone is administered in any of the ways
known in the art to alleviate an inflammatory conditions, for example,
in any dosage regimen and by any of the known routes of systemic
administration.
(d) Bronchodilation (Anti-asthma)
These novel analogs disclosed herein are also useful in the
treatment of asthma. For example, these compounds are useful as
bronchodilators or as inhibitors of mediator-induced bronchocon-
striction, such as SRS-A, and histamine which are released from cells
activated by an antigen-antibody complex. Thus, these compounds
control spasm and facilitate breathing in conditions such as bronchial
bronchitis, bronchiectasis, pneumonia and emphysema. For these pur-
poses, these compounds are administered in a variety of dosage forms,e.g., orally in the form of tablets, capsules, or liquids; rectally in
the form of suppositories, parenterally, subcutaneously, or intra-
muscularly, with intravenous administration being preferred in emer-
gency situations; by inhalation in the form of aerosols or solutions
for nebulizers; or by insufflation in the form of powder. Doses in
the range of about 0.01 to 5 mg per kg of body weight are used 1 to 4
times a dayg the exact dose depending on the age, weight, and condi-
tion of the patient and on the frequency and route of administration.
For the above use these CBA analogs can be combined advantageously
with other anti-asthmatic agents, such as sympathomimetics (isopro-
terenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theo-
phylline and aminophylline); and corticosteroids (ACTH and predniso-
lone).
tr~d~ ma rk
~2~'712 3704/3803/3823/3833/3879/3893
-20 -
These compounds are effectively administered to human asthmapatients by oral inhalation or by aerosol inhalation. For adminis-
tration by the oral inhalation route with conventional nebulizers or
by oxygen aerosolization it is convenient to provide the instant
5 active ingredient in dilute solution, preferably at concen~rations of
about one part of medicament to from about 100 to 200 parts by weight
of total solution. Entir~ly conventional additives may be employed to
stabilize these solutions or to provide isotonic medial for example,
sodium chloride, sodium citrate, citric acid, sodium bisul fite, and
10 the like can be employed. For administration as a self-propelled
dosage unit for administering the active ingredient in aerosol form
suitable for inhalation therapy the composition can comprise the
active ingredient suspended in an inert propellant (such as a mixture
of dichlorodi fl uoromethane and dichlorotetrafl uoroethane) together
15 with a co-solvent, such as ethanol, flavoring materials and s~abili-
zers. Suitable means to ernploy the aerosol inhalation therapy tech-
nique are described fully in United States Patent 3,868~691, for
example.
When Xl is -COORl, the novel CBA anal ogs so described are used
20 for the purposes described above in the free acid form, in ester form,
or in pharmacologically acceptable sal t form. When the ester form is
used, the ester is any of those within the above definition of Rl.-
However, it is preferred that -the ester be al kyl of one to 12 carbon
atoms, inclusive. Of the alkyl esters, methyl and ethyl are espec-
25 ially preferred for optimum absorption of the compound by the body orexperimental animal system; and straight-chain octyl, nonyl, decyl,
undecyl, and dodecyl are especially preferred for prolonged activity.
Pharmacologically acceptable salts of the novel prostaglandin
analogs of this invention for the purposes described above are those
30 with pharmacologically acceptable metal cations, ammonia, amine
cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived from the
alkali metals, e.g., lithium, sodium, and potassium, and from the
alkaline earth metals, e.g., magnesium and calcium, although cationic
35 forms of other metals, e.g., aluminum, 7inc~ and iron are within the
scope of this inven~ion.
Pharmacologically acceptable amine cations are those derived from
primary, secondary, and tertiary amines. Examples of suitable amines
~2~ %
~ 3704/3803/3823/3833/3879/3~93
-21-
are methyl amine, dimethyl amine, trimethyl amine, ethyl amine, dibutyl-
amine, triisopropylamine, N-methyl hexyl amine, decyl amine, dodecyl~
amine, allyl amine, crotylamine, cyclopentyl amine, dicycl ohexyl amine,
benzyl amine, dibenzyl amine, a- phenylethyl amine, ~-phenylethyl amine,
5 ethylenediamine, diethylenetriamine, adamantylamine, and the like
aliphatic, cycloaliphatic, araliphatic amines containing up to and
including about 18 carbon atoms9 as well as he~erocyclic amines, e.g.,
piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl
derivatives thereto9 e.g., l-methyl piperidine, 4-ethylmorpholine,
10 1-isopropyl pyrrolidine, 2-methyl pyrrolidine, 1,4-dimethyl pi perazine,
2-methylpiperidine, and the like as well as amines containing water-
solubilizing or hydrophilic groups, e.g., mono, di-, and triethanol-
amine, ethyl diethanol amine, N-butyl ethanolamine, 2-amino-1-butanol,
2-amino-2-ethyl-1,3-propanediol, 2-amino~2-methyl l-propanol, tris-
(hydroxymethyl ) aminomethane, N-phenylethanolamine, N-(p-tert-amyl-
phenyl)-diethanolamine, galactamine, N-methylglycamine, !~I-methyl-
glucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the
like. Further useful amine salts of the basic amino acid salts, e.g.,
l ysine and arginine.
Examples of suitable pharmacologically acceptable quaternary
ammonium cations are tetramethylammonium, tetraethylammonium, benzyl-
trimethylammonium9 phenyltriethylammonium, and the like.
When Xl is -CH2NL2L3, the novel C8A analogs so described are used
for the purposes described in either free base or pharmacologically
25 acceptable acid addition salt form.
The acid addition salts of the 2-decarboxy-2-aminomethyl- or
2-(substituted aminomethyl)-CBA analogs provided by this invention are
the hydrochl orides, hydrobromides, hydriodides9 sul fatesg phosphates,
cyclohexanesul famates, methanesul fonates, ethanesul fonates, benzene-
30 sul fonates, to1 uenesul fonates and the like, prepared by reacting theCBA analog with the stoichiometric amount of the acid corresponding to
the pharmacologically acceptable acid addition salt~
To obtain the optimum combination of biological response specifi-
city, potency, and duration of activity, certain compounds within the
35 scope of this invention are preferred~
It is preferred that in the X1-terminated side chain for inter-
p-phenylene-CBA compounds, g be zero, for inter-m-phenylene-CBA com-
pounds g be zero or one (especially zero), and for inter-o-phenyl ene
- - 3L~ L~7~ 3704/3803/3823/3833t3879/3893 -22-
C3A compounds g be zero, one, or 2 (especially one)~ Inter-o- and
in~er-m-phenylene-C~A compounds, especially inter~m-phenylene-CBA
compounds are preferred. Moreover wh2n Zl is -CH2-~CH2)f-C(R2)2~ f is
preferably one and R2 is preferably hydrogen. When R17 is (Cl-C4)-
alkyl, Rl7 is preferably methyl. Further, when the C 12 side chain
contains -CmH2m-CH3, it is preferred that m be 3, 4, or 5, most
preferably 3. When m is 5, more straight chain isomeric forms are
preferred, especially methyl-substituted butyl. Furtherg it is pre-
ferred that, when R7 is aromatic, R7 be phenoxy, phenyl, or benzyl,
including substituted forms thereof. For those compounds wherein R7
is substituted phenoxy or phenylalkyl, it is preferred there be only
one or 2 substituents selected from the group consisting of chloro,
fluoro, or trifluoromethyl. Further, for those compounds wherein R7
is aromatic, it is preferred that R3 and R4 both be hydrogen.
Most expecially preferred to biological potency are formula X
CBA2 analogs exhibiting the same C-5 isomeric configuraton as C~A2
itself.
Especially preferred are those compounds which satisfy two or
more of the above preferences. Further, the above preferences are
expressly intended to describe the preferred compounds within the
scope of any generic formula of novel CBA analogs disclosed herein,
Those protective groups within the scope of R1o are any group
which replaces a hydroxy hydrogen and is neither attacked by nor is
reactive to the reagents used in the transformations used herein as a
hydroxy is and which is subsequently replaceable by acid hydrolysis
with hydrogen in the preparation of the prostaglandin-type compounds.
Several such protective groups are known in the art, e.g., tetra-
hydropyranyl and substituted tetrahydropyranyl. See for reference
E.J. Corey, Proceedings of the Robert A. Welch Foundation Conferences
on Chemical Research, XII Organic Synthesis, pgs. 51-79 (1969). Those
blocking groups which have been found useful include:
(a) tetrahydropyranyl;
(b) tetrahydrofuranyl;
(c) a group of the formula -C(ORll)(Rl2)-CH(Rl3)(Rl4), wherein
Rll is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to
10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclu~
sive, phenyl or phenyl substituted with one to 3 alkyl of one to 4
carbon atoms, inclusive, wherein Rl2 and Rl3 are alkyl of one to 4
7 :~
3704/3803/3823/3~33/3879/3893
2~-
carbon atoms, inclusive, phenyl, phenyl substituted with one, 2 or 3alkyl of one to 4 carbon atoms, inclusive, or when Rl~ and R13 are
taken together -(CH2)a- or when Rl2 are Rl3 are taken together
-(CH2)b-0-(CHz)c, wherein a is 3, 4, or 5 and b is one, 2, or 3, and c
is one~ 2, or 3, with the proviso that b plus c is 2, 3, or 4, with
the further proviso that Rl2 and Rl3 may be ~he same or different, and
wherein Rl,; is hydrogen or phenyl; and
(d) silyl groups according to R289 as qualified hereinafter.
When the protective group Rlo is tetrahydropyranyl, the tetra~
hydropyranyl ether derivative of any hydroxy moieties of the CBA-type
intermediates herein is obtained by reaction of the hydroxy-containing
compound with 2,3-dihydropyran in an inert solvent, e.g~, dichloro~
methane, in the presence of an acid condensing agent such as p-tolu-
enesulfonic acid or pyridine hydrochloride. The dihydropyran is used
in large stoichiometric excess, preferably 4 to 100 times the stoich-
iometric amount. The reaction is normally complete in 1ess than an
hour at 20-50C.
When the protectiYe group is tetrahydrofuranyl, 2,3-dihydrofuran
is used, as described in the preceding paragraphg in place of the
2,3-dihydropyran.
When the protective group is of the formula
-C(OR.ll)(Rl2)-CH(Rl3)(Rl4), wherein Rl1, Rl2, Rl3, and R~ are as
defined above; a vinyl ether or an unsaturated cyclic or heterocyclic
compound, e.g;, 1-cyclohexen-1-yl methyl ether, or 5,6-dihydro-4-
methoxy~2H-pyran is employed. See C.B~ Reese, et al., J. American
Chemical Society 89, 3366 (1967). The reaction conditions for such
vinyl ethers and unsaturated compounds are similar to those for
dihydropyran above.
R28 is a silyl protective group of the formula -Si(Gl)3. In some
cases, such silylations are general, in that they silylate all
hydroxyls of a molecule, while in other cases they are selective, in
that while one or more hydroxyls are silylated, at least one other
hydroxyl remains unaffected. For any of these silylations, silyl
groups within the scope of -Si(Gl)3 include trimethylsilyl, dimethyl-
phenylsilyl, triphenylsilyl, t-butyldimethylsilyl, or methylphenyl-
benzylsilyl. With regard to G1, examples of alkyl are methyl, ethyl,
propyl, isobutyl, butyl, sec-butyl, tert-butyl, pentyl, and the like~
Examples of aralkyl are benzyl, phenethyl, -phenylethyl, 3-phenyl-
-- ~ 3~ 7~ ~ 3704/3803/3823/3833/3879/3~93
-24-
propyl, a-naphthylmethyl, and 2-(-naphthyl)ethyl. Examples of
phenyl substituted with halo or alkyl are p-chlorophenyl 9 m-fluoro-
phenyl, o-tolyl, 2~4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-
methylphenyl, and 2,4-dichloro-3-methylphenyl.
These silyl groups are known in the art. See for example, Pierce
"Silylation of Organic Compounds," Pierce Chemical Company, Rockford,
Ill. (1968). When silylated products of the charts below are
intended to be subjected to chromatographic purification, then the use
of silyl groups known to be unstable to chromatography (e.g. tri-
methylsilyl) is to be avoided. Further, when silyl groups are to be
introduced selectively, silylating agen~s which are readily available
and known to be useful in selective silylations are employed. For
examp1e, t-butyldimethylsilyl groups are employed when selective
introduction is required. Further, when silyl groups are to be
selectively hydrolyzed in the presence of protective groups according
to Rlo or acyl protective groups, then the use of silyl groups which
are readily available and known to be easily hydrolyzable with
tetra-n-butylammonium fluoride are employed. A particularly useful
silyl group for this purpose is t-butyldimethylsilyl, while other
silyl groups (e.g. trimethylsilyl) are not employed when selective
introduction and/or hydrolysis is required.
The protective groups as defined by Rlo are otherwise removed by
mild acidic hydrolysis. For example, by reaction with (1) hydro-
chloric acid in methanol; (2) a mixture of acetic acid, water, and
tetrahydrofuran, or (3) aqueous citric acid or aqueous phosphoric acid
in tetrahydrofuran, at temperatures below 55 C., hydrolysis of the
blocking group is achieved.
R3l is a hydroxy-hydrogen protective group, as indicated above.
As such, R3l may be an acyl protective group according to Rg, an acid
hydrolyzable protective group according to Rlo, a silyl protective
group according to R28, or an arylmethyl hydroxy hydrogen replacing
group according to R34.
Acyl protective groups according to Rg include:
(a) benzoyl;
(b) benzoyl substituted with one to 5 alkyl of one to 4 carbon
atoms, inclusive, or phenylalkyl of 7 to 12 carbon atoms~ inclusive,
or nitro, with the proviso that not more than two substituents are
other than alkyl, and that the total number of carbon atoms in the
~LZ~L~ 370~/3803/3823f3833/3~79/3~93
-25-
substituents does not exceed 10 carbon atoms, with the further proviso
that the substituents are the same or different;
(c) benzoyl substituted with alkoxycarbonyl of 2 to 5 carbon
atoms, inclusive;
(d) naphthoyl;
(e) naphthoyl substituted with one to 9, inclusive, alkyl of one
to 4 carbon atoms, inclusive, phenylalkyl oF 7 to 10 carbon atoms,
inclusive, or nitro, with the proviso that not more than two substi-
tuents on either of the fused aromatic rings are other than alkyl and
that the total number of carbon atoms in the substituents on either of
the fused aromatic rings does not Pxceed 10 carbon atoms, with the
further proviso that the various substituents are the same or differ-
ent, or
(f) alkanoyl of 2 to 12 carbon atoms, inclusive.
In prepariny these acyl derivatives cf a hydroxy-containing
compound herein, methods generally known in the ar~ are employedO
Thus, for example, an aromatic acid of the formula RgOH, wherein Rg is
as defined above (e,g., benzoic acid), is reacted with the hydroxy-
containing compound in the presence of a dehydrating agent, e.g. p-
toluensulfonyl chloride or dicyclohexylcarbodiimide; or alternatively
an anhydride of the aromatic acid of the formula (Rg)OH, e.g., benzoic
anhydride, is used.
Preferably, however, the process described in the above paragraph
proceeds by use of the appropriate acyl ha1ide, e.g., RgHal, wherein
Hal is chloro, bromo, or iodo. For example, benzoyl chloride is
reacted with the hydroxyl-containing compound in the presence of a
hydrogen chloride scavenger, e.g. a tertiary amine such as pyridine,
triethylamine or the like. The reaction is carried out under a
variety of conditions, using procedures generally known in the art.
Generally mild conditions are employed: 0-60C., contacting the
redctants in a liquid medium (e.g., excess pyridine or an inert
solvent such as benzene, toluene, or chloroform). The acylating agent
is used either in stoichiometric amount or in substantial stoichio-
metric excess
.
As examples of Rg, the following compounds are available as acids
(RgOH), (Rg)20, or acyl chlorides (RgCl) benzoyl; substituted ben-
zoyl, e~g.9 (2-, 3-, or 4-)methylbenzoyl, (2-, 3 , or 4-)ethylbenzoyl,
(2-, 3-, or 4-)isopropylbenzoylg (2-, 3-, or 4-)tert-butylbenzoyl,
~L2~ 3704/3803/3823/3833/3879/3893
-26-
2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl ~ 2-isopropylto1uyl, 2,4,6-
trimethylbenzoyl, pentamethylbenzoyl, phenyl(2-, 3-, or 4-)toluyl,
(2-, 3, or 4-)phenethyl benzoyl, (2-, 3-, or 4-)nitrobenzoyl, (2,4,
2,5-, or 2,3-)dini~robenzoyl 9 2,3-dimethyl-2-nitrobenzoyl, 4,5-di-
5 methyl -2-nitrobenzoyl, 2-nitro-6-phenyl ethyl benzoyl, 3-ni~ro-2-
phenethylbenzoyl, 2-nitro-6-phene~hylbenzoyl, 3-nitro-2-phenethyl-
benzoyl, mono esterified phthaloyl, isophthaloylg or terephthaloyl;
1- or 2-naphthoyl; substituted naphthoyl, e.g., (2-, 3-, 4-, 5-, 6-,
or 7-)methyl-1-naphthoyl, (2- or 4-)ethyl-1-naphthoyl, 2-isopropyl-
10 1-naphthoyl, 4,5-dimethyl-1-naphthoyl ~ 6-isopropyl-4-methyl-1-
naphthoyl ~ 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-)-nitro-1-
naphthoyl, 4,5-dinitro-1-naphthoyl, (3, 4-, 6-, 7-, or 8-)-
methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 8-)nitro-2-
naphthoyl and acetyl.
There may be employed, therefore, benzoyl chloride, 4-nitro-
benzoyl chloride, 3,5-dinitrobenzoyl chloride, or the like, i.e~ RgC1
compounds corresponding to the above Rg groups. If ~he acyl chl oride
is not available, it is prepared from the corresponding acid and
phosphorus pentachl oride as is known in the art. It is preferred that
20 the RgOH, (Rg)20, or RgC1 reactant does not have bulky hindering sub-
stituents, e.g. tert-butyl on both of the ring carbon atoms adjacent
to the carbonyl attaching site.
The acyl protective groups, according to Rg, are removed by de-
acylation. Alkali metal carbonate or hydroxide are employed effec-
25 tively at ambient temperature for this purpose. For example, potas-
sium carbonate or hydroxide in aqueous methanol at about 2S C is ad-
vantageously employed.
R3~ is defined as any arylmethyl group which replaces the hydroxy
hydrogen of the intermediates in the preparation of the various CBA
30 analogs herein which is subsequently replaceable by hydrogen in the
processes herein for preparation of these respective prostacyclin
analogs, being stable with respect to the various reactions to which
R34-containing compounds are subjected and being introduced and sub-
sequently removed b~y hydrogenolysis under conditions which yield
35 substantially quantitative yields of desired products~
Exampl es of arylmethyl hydroxy-hydrogen repl acing groups are
(a) benzyl;
(b) benzyl substituted by one to 5 alkyl of one to 4 carbon
^ ~L ~ 3704/3803/3823/3833/3879/3893
-27-
atoms~ inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7
to 12 carbon atoms, inclusive, with the further proviso that the
various substituents are the same or different;
(c) benzhydryl;
(d) benzhydryl substituted by one to 10 alkyl of one to 4 carbon
atoms, inclusive, chloro, bromo9 iodo, fluorog nitro, phenylalkyl of 7
to l2 carbon atoms, inclusive, with the further proviso that the var-
ious substituents are the same or different on each of the aromatic
rings;
(e) trityl;
(f) trityl substituted by one to 15 alkyl o~ one to 4 carbon
atoms, inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7
to 12 carbon atoms, inclusive, with the further proviso that the
various substituents are the same or different on each of the aromatic
rings.
The introduction of such ether linkages to the hydroxy-containing
compounds herein, particularly the benzyl or substituted benzyl ether
proceeds by methods known in the art, for example by reaction of the
hydroxy-containing compound with the benzyl or substituted benzyl
halide (chloride, bromide, or iodide) corresponding to the desired
ether. This reaction proceeds in the presence of an appropriate
condensing agent (e.g., silver oxide). The mixture is stirred and
heated to 50-80C. Reaction times of 4 to 20 hours are ordinarily
sufficient.
The Charts herein describe the methods whereby the novel inter-
mediates and end products of the present specification are prepared by
the novel processes herein. ~ith respect to these charts, 9, n, L1,
M1, M6, R7, R8, Rlo, R1s, R16, R17, R1g, R20, R21~ ~22~ R23~ and R24~
R2O~ R31~ X1, Y1, Z1, and Z~ are as defined above. R37 is the same as
RL~7~ but other than -CH20H. R38 iS -OR31, hydrogen, or -CH20R31,
wherein R3l is defined as above. R27 is the same as R7 except that
-(CH2)2-CH(OH)-CH3 is -(CH2)2-CH(OR1o)~CH3~ R37 is the same as R17,
but other than hydrogen. Ac is acetyl. Z2 is the same as Z1 but not
-(Ph)-(CH2)9-. Z3 is the same as Z1, but not trans-CH2-CH=CH-.
With respect to Chart A, a method is provided whereby the known
formula XXI bicyclic lactone is transformed to the carbacyclin inter-
media~e of formula XXV useful in the preparation of formula X C~A
compounds wherein R17 is alkyl or Rl6 and R17 taken togeth~r are
L'71~
-- 3704/3803/3823/3833/3879/3893
-28-
methano or a second val ence bond between C-6a and C-9. With respect
to Chart A, the formul a XXI compound is transformed to the formula
XXII compound by treatment with the anion of dimethyl
methyl phosphonate. Methods for such a reaction are known in the artO
5 See Dauben, W.G. 9 et al., JACSg 97:4973 (1975), describing a reaction
of this type.
The formula XXII l actol is transformed to the formul a XXIII
diketone by oxidation methods known in the art. For example, Collins
reagent or Jones reagent is employed in this oxidative transformation.
The formula XXXII diketone is cycllzed to the formula XXIV com-
pound by an intramol ecul ar Horner-Emmons reaction. The chemical
methodology for analogous transformations is known in the art. See
Piers, E., et al., Tetrahedron Letters, 3279 (1979) and Cl ark, R.~.,
et al., Synthetic Communications 5:1 (1975).
The formula XXIV compound is transformed to the novel formula XXV
compound wherein R16 is hydrogen and R37 is alkyl by treatment wi~h
lithium dialkyl cuprate. The lithium dialkyl cuprate is prepared by
conventional means, e.g.g reaction of anhydrous copper iodide in
diethyl ether with an alkyllithium in diethyl ether, and thereaf~er
20 reacted with the formula XXIV compounds, e.g., in diethyl ether.
The formula XXIV compound is transferred to ~he novel formula XXV
compound wherein R16 and R37 taken together are methylene (-CH2-) by
one of two methods. By the first method, the formula XXV compound is
prepared by treatment of the formula XXIV compound with the anion of
25 trimethyloxosulfonium iodide. See for reference E. J. Corey, et al.,
JACS 87:1353 (1965). By this method, the anion is conveniently gener-
ated by treatment of trimethyloxosulfonium iodide in sodium hydride.
By a second method, the formula XXIV compound is converted to the
formul a XXV compound wherein R16 and R37 taken together are methyl ene
30 by first converting the formula XXIV compound to the corresponding
formul a XXVI hydroxymethyl compound by photochemical addition of
methanol (e.g., see G~ L. Bundy, Tetr. Lett, 1957, 1975), thereafter
treating the resulting hydroxymethyl compound with an excess (e.g.,
two equivalents) of p-toluenesulfonyl chloride in a tertiary amine
35 base to yield the corresponding formula XXVII tosylate, and finally
treating the resulting formula XXVII tosylate with base (e.g,,
potassium t-butoxide) to yield the formula XXV cyclopropyl compound~
With respect to Chart B, a method is provided whereby the formula
3704/3803/3~23/3833/3879/38~3
-29-
XXXI compound prepared in accordance with methods of Chart A is trans-
formed to the novel CBA2 anal ogs of formula XXXVI.
The formul a XXXI compound is transformed to the formul a XXXVI
compound by methods known in the art for preparing carbacyclin. See
S for example, British published applications re~erred to above. Alter-
natively, the formula XXXI compound is reacted with formula XXXII com-
pound and thereby successively transformed to the formul a XXXIII,
formula XXXIV and formula XXXV compounds.
The reaction of the formul a XXXI compound empl oyiny the formul a
10 XXXII compound is accomplished by methods known in the art. See
Moersch, G.W., J. Organic Chemistry, 36:1149 (1971) and Mulzerl J., et
al., Tetrahedron Letters, 2949 (1978). The formula XXXII reactants
are known in the art or are prepared by methods known in the art. See
Example 4 describing one such method of prepara~ion of a formula XXXII
15 compound.
The formula XXXIII compound is then transformed to the formul a
XXXIV compound by decarboxylative dehydration. Procedures for this
reaction are known in the art. See Eschenmoser, A., et al., Helv.
Chim. Acta. 58:1450 (1975), Hara, S., et al., Tetrahedron Letters,
20 1545 (1975) and Mul zer, J., et al., Tetrahedron Letters, 2953 (1978)
and 1909 (1979).
Finally, the formula XXXV compound is prepared from formula XXXIV
compound by selective desilylation. Such procedures are known in the
art and typically employ the use of tetra-n-butyl ammonium fluoride
25 and tetrahydrofuran. See Corey, E.J., et al., JACS 94:6190 (1972).
The formula XXXV compound is transformed to various acids,
esters, amides, and amines of a formula XXXVI by methods known in the
art. Particularly useful in this regard are methods described in the
aforementioned British published speci~ications describing the prepa-
30 ration of carbacyclin analogs.
The preparation of formul a XXXVI compounds from the formul a XXXVcompounds proceeds by, for example, oxidation to the corresponding
carboxylic acid, followed by hydrolysis of any protective groups at
the C-ll or C-15 position of the molecule. Such carboxylic acids are
35 then esterified by conventional means or amidized by conventional
means. Such amides may, for example, then be reduced to corresponding
amines (Xl is -CH2NL2L3 by reduction by lithium aluminum hydride. See
U.S. Patent 4,073,808. In a preparation of the primary alcohol s
3704/3803/3823/3833/3879/3893
-30-
according to formula XXXVI from the formula XXXV compound, hydrolysis
of any protective groups at C-ll or C-15 yields such products
directly~ Hydrolysis is accomplished by procedures described above~
e,g., mild acidic conditions a-t elevated temperatures.
Chart C provides a method whereby the known formula XLI compounds
are transformed to the formula XLIV aldehydes employed in Chart D in
the preparation of inter-phenylene-CBh2 compounds therein.
With respect to Chart C, the formula XLII compound is prepared
from the formul a XLI compounds by reduction. Conventional methods
10 known in the art ~or the trans~ormation of carboxylic acids to corres-
ponding primary al cohol s are empl oyed. For exampl e 3 one extremel y
useful conventional means for this reduction is employing lithium
aluminum hydride as a reducing agent.
The formula XLIII compound is then prepared from the formula XLII
15 compound by monosilylation. Particularly, formula XLIII compounds are
prepared wherein R28 represents a relatively stable silyl group, most
preferably being t-butyldimethylsilyl or phenyldimethylsilyl. Other
silyl groups, particularly trimethyl-silyl (TMS) are not preferred for
use in connection with the methods of Chart C.
The formula XLIII monosilyl derivatives are prepared from the
formula XLII compound by reacting the formula XLII compounds with
about an equal molar amount of the silylating agent. For example,
when R28 is t-butyldimethylsilyl, a single equivalent of t-butyl-
dimethyl silyl chl oride is empl oyed in the transformation. Accord-
25 ingly, there are prepared both monosilyl derivatives of the formula
XLII compound as well as the bis-silyl derivatives corresponding to
formula XLII. From this mixture of products, the formula XLIII
compound is recovered by conventional means, e.g., column chroma-
tography. Otherwise, the silylation proceeds under conditions con-
30 ventionally employed for silylating hydroxyl groups. Refer to the
discussion hereinabove.
The formula XLIV compound is then prepared from the formula XLIII
compound by oxidation of the formula XLIII alcohol to the
corresponding aldehyde. Conventional oxidizing agents are employed,
35 e.g., manganese dioxide.
Chart D provides a method whereby the known formul a LI ketones
are transformed to the formula LX inter-phenylene C~A2 analogs dis-
closed herein.
~2~L~
3704/3803/3823/3833/3879/3893
-31~
In accordance with Chart D the formula LII compound is prepared
from the formula LI compound by reduction of the ~ormula LI ketone to
the corresponding secondary alcohol. This reduction proceeds by
conventional means, employing readily available reducing agents.
Accordingly, sodium, potassium, or li~hium borohydride is conveniently
employed in this reduction.
Thereafter, the formula LII alcohol is transformed to the corres-
ponding mesylate (methanesulfonate)O Conventional methods for the
transformation of alcohols to corresponding mesylates are employedO
Thus, the formula LI I alcohol is reacted wi~h methane-sulfonyl chlor-
ide in the presence of a tertiary amine (e.gO~ tri~ethylamine~ in the
preparation of the formula LIII compound.
Other sulfonyl derivatives corresponding to the formula LII
alcohol may be employed in place of the formula LIII compound in the
transformations of Chart ~. These other sul~onyl derivatives are
preferaoly those derived from readily available sulfonylating reag-
ents, i.e., the corresponding sulfonyl chlorides. One especially
important alternative to the formula LIII compound is the tosylate
(toluenesulfonate) corresponding to the for~ula LII compound.
The formula LIII compound, or an alternate sulfonate corres-
ponding thereto, is transformed to the formula LIV compound by treat-
ment with sodium lithium or potassium thiophenoxide. The thiophenox-
ide is conveniently prepared just prior to the transformation by
mixing approximately equal molar amounts of thiophenol and base, e.g.,
potassium t-butoxide.
This formula LIV compound is then oxidized to the corresponding
formula LV compound by oxidation with a readily available o~idizing
agent such as m-chloroperbenzoic acid.
The formula LV compound is then condensed with the formula XLIV
compound prepared according to Chart C by first treatment of the
formula LV compound with a strong base, e.g. 5 n-butyllithium, to
generate the anion corresponding to the formula LV compound, treatment
of the corresponding anion with the aldehyde of formula XLIV and
finally treating the resulting adduct with acetic anhydride to yield
the formula LVI acetyl compound~
The formula LVI compound is then transformed to the formula LVII
compound by reaction with a sodium amalgamD Methods by which the
formula LVI I ol efin is formed from the formula LV compound are analo-
3~ 2 370~/3803/3823/3833/3879/3893-32-
gous to known methods described by Kocienski, P.J., et al., "Scope andStereochemistry of an Ol efin Synthesis from B-Hydroxysul phones", JCS
Perkin I, 829-834 (1978).
The formul a LVII compound is then transformed to the ~ormul a
5 LVIII compound by selective hydrolysis of the silyl group according to
R28. Conventional means for this hydrolysis are employed, e.g.,
tetra n-butyl ammonium fl uoride. Refer to the discussion above for a
discription of this hydrolysis.
The formul a LVIII C-5 diastereomers thusly prepared are con-
10 veniently puri~ied into (5-E) and (5-Z) isomeric forms. This trans^
formation proceeds by conventional means, e,g., column chromatography.
Thereafter either the (5E) or (5Z) isomer of formula LVIII is
transformed to the formul a LIX carboxylic acid or ester by conven-
tional oxidation, followed by op~ional esterification. One especially
15 convenient means of oxidation is employing the Jones reagent5 although
other oxidizing agents are employed. Esterification then proceeds by
methods hereinafter described.
Finally, the formul a LX products are prepared from the formul a
LIX compound by first hydrolyzing the protective groups under acidic
20 conditions, e.g., mixtures of water, tetrahydrofuran, and acetic acid.
Thereafter, ~he formula LIX acids and esters are transformed to var-
ious other C-1 derivatives by methods hereinafter described.
One espec~ally convenient means of preparing the formula LX com-
pound as a free carboxylic acid (X1 is -COOH), is by purification of
25 the corresponding methyl ester, followed by saponiFication under basic
conditions (e.g., the treatment with potassium carbonate or sodium or
potassium hydroxide).
Chart L provides a method whereby the known formula LXI compound
i s transformed into formul a LXII I i ntermediate useful i n the
30 preparation of the novel CBA2 analogs.
The procedures for the trans-formation of the formula LXI compound
to the formula LXIII compound are analogous to those describing the
transformation in Charts A, B, and D of the formula XXI compound to
the formul a XXXVI and LX compounds (i.e~, corresponding to the
35 transformation of formula LXI compound to the formula LXII compound is
the transformation in Chart A of the formul a XXI compound to the
formula XXV compound and corresponding to the transformation of the
formul a LXI I compound to the formul a LXIII compound i s the
71;~
-~~ 370~/3803/3823/3833/3879/3893
-33-
transforma~ion in Chart D of the formula LI compound to the formula LX
compound.). For convenience, the protective groups R31 and R38 may be
the same or different, although preferably such protective groups are
different, whereby the hydrolysis of a protective group according to
5 R3l is accomplished in the presence of a protective group according to
R38.
Chart F then provides a method whereby the formula LXXI compound
prepared according to Chart E is transformed to the formula LXXII
carbacyclin anal og in accordance with the present invention~ '~ith
10 respect to Chart F, the formula LXXI compound is transformed to the
formula LXXII compound by selective hydrolysis of the protective group
according to R3l. Thereafter, the formula LXXII compound is
transformed to formula LXXIII compound by methods known in the art,
e.g., oxidation of the formula LXXII primary alcohol to the corres-
15 ponding aldehyde, Wit~ig oxylacylating the aldehyde, and reduction of
the resulting ketone to the secondary or tertiary alcoho1 correspond-
ing to Ml. For an example of the various transformations employed
according to Chart F, see Chart A (part VI) of U.S. Patent 4,107,427,
issued 15 August 1978;
Chart G provides a method whereby the novel formul a LXXXI
intermediate, prepared according to Chart A, is transformed to the
formul a LXXXVIII and LXXXI X i somers of the novel C-6a- and/or
C-9-substituted CBA2 anal ogs.
With respect to Chart G, the formula LXXXIII compound is
25 prepared from the formula LXXXI ketone by a Wittig ~-carboxyalkylation
employing a formula LXXXII triphenylphosphoniwn compound. The Wittig
reaction is undertaken under conventional reaction conditions for
preparing prostaglandin-type substances. The formul a LXXXIII compoun~
is then optionally hydrolyzed to yield the formula X carboxylic acid
30 products or employed in the further transformations of Chart G in
ester form.
The formula LXXXIII compound thusly prepared is thereafter
preferably separated directly into C-5 isomers of formulas LXXXVIII
and LXXXIX (e.g., by chromatographic means followed by hydrolysis of
35 any protective groups at C-ll or C~15 position of the molecule), or is
alternatively transformed to the formula LXXXIV ester by conventional
esterification techniques, e.g., ethereal diazomethane treatment or
treatment with methyl iodide. The formul a LXXXIV ester is then
i2
3704/3803/3823/3833/3879/3893
-3~-
reduced to the corresponding primary alcohol by reduction with a
suitab1e reducing agen~, e.g,, lithium aluminum hydride, by methods
known in the art for preparing prostaglandin-type primary alcohols
from corresponding prostaglandin esters.
The formula LXXXV compound represents an especially convenient
intermediate for the facile separation of the C-5 diastereomers.
Accordingly5 the formula LXXXV compound may be separated by conven-
tional means of separation of diastereomeric mixtures, e.g., column
chromatography~ whereby the formula LXXXVI and formula LXXXVII com-
pounds are prepared in isomerically pure form~ These primary alcohols
are then conveniently transformed to the formula LXXXVIII and LXXXIX
products by methods desoribed above. Refer to the transformations of
the formula XXXV compound to the formula XXXVI compound in Chart B.
Chart H provides a method whereby the formula XCVII 5-fluoro-CBA2
cornpounds are prepared from the formula XCIII CBA2 intermediates known
in the art. See9 for example, British Published Application
2,014,143, especially the discussion relative to step (b) of Chart A
therein. This formula XCI sulfoximine i5 transformed to the formula
,. 1 XCII flu~r~i~nated sulfoximine by first generating an anion of the
formula ,YCII compound, e.g~ 9 by treatment with n-butyllithium in
hexane, and treating the resulting anion with a fluorine source.
Particularly preferred as a source of fluorine is perchloryl fluoride
(FCl03).
The formula XCII compound thusly prepared and the known formula
25 XCIII compound described above are then employed in the preparation of
the formula XCIV compound by known methods. Refer again to step (b)
of Chart A of 3ritish Published Application 2,014,143.
The formula XCIV compound thusly prepared is then transformed to
the formula XCV primary alcohol by hydrolysis under mild acidic
conditions (e.g., mixtures of acetic acid, water, and tetrahydrofuran)
as is known in the art. Thereafter, the formula XCV primary alcohol
is oxidized to the corresponding formula XCVI carboxylic acid employ-
ing conventional means. For example, treatment with oxygen and an
aqueous suspension of platinum oxide hydrogenated at ambient tempera-
ture and pressure yields the formula LXXVI carboxylic acid. There-
after, the formula XCVI compound is transformed into the various
formula XCVII products by derivatization or transformation of the
carboxyl group of the formula XCVI compound.
~ ~L~ 3704/3803/3823/3833/3879/3893
-35
The C-5 isomers of the formula XCIV to formula XCVII compounds
are conveniently separa~ed at any step during the process of Chart H,
but are most conveniently and preferably separated from the formula
XCIV diastereomeric mixture. Conventional means, e.g., column
chromatography, are employed in the separation.
Chart I provides an optional method whereby the known formula CI
compound is transformed to the formula CIII products herein. ~ith
respect to Chart I, the formula XCII iS prepared from the formula XCI
compound by the procedure described in Chart H for the preparation of
the formula XCVII compound from the formula XCIII compound. This
formula CII CBA2 intermediate is then transformed to the formula CIII
compound by the procedures described in Chart F for the transformation
of the formula LXXI to the formu1a LXXIII compound.
Chart J provides the preferred methods for preparing the formula
X CBA analogs wherein Zl is trans-CH2-CH=CH-. With respect to Chart
J, Rl therein is other than hydrogen or a cation, preferably being
lower alkyl. The formula CXIV is prepared from the formula CXI
compound by first preparing the ~-phenylselenyl derivative thereof,
dehydrophenylselenizing, whereby the formula CXI I I ~, ~-unsaturated
ester is prepared. This ester is then transformed to the formula CXIV
free acid (Xl is -COOH) by saponification and this free acid is trans-
formed to the various other formula CXIV compounds as indicated in
Chart H (refer to the transformation of the formula XCVI compound to
the formula XCVII compound).
Chart K provides the preferred method whereby the formula VI C~A
intermediates wherein Zl is trans-CH2-CH=CH- are prepared. With
respect to Chart K, the formula CXXI compound is transformed to the
formula CXXIII compound by methods analogous to those described in
Chart J for the preparation of the formula CXIV compound from the
formula CXI compound.
For a detai1ed description of the methodology employed in Charts
J-K, refer to the discussion in British Patent 2,014,143, and
references cited therein.
Charts L-O provide methods whereby CBA2 intermediates and analogs
are employed in the synthesis of corresponding CBAl intermedia~es and
analogs.
Chart L provides the preferred method for preparing the formula
VII CBAl intermediates wherein Zl is trans-CH2-CH=CH-. With respect
2 3704/3803/3823/3833/3879/3893
-36-
to Chart L the formul a CXXXI compound, prepared as the formul a CXXI Icompound of Chart K, is reduced to the formula CXXXII compound by
conventional methods~ For a discussion of such methods, and general
methodologies for transformlng CBA2 intermediates and analogs to
5 corresponding CBA1 intermedla~es and analogs, refer to British
Published Application 2,017,699. For example, catalytic hydrogenation
with conventional catalys~s under atmospheric pressure is empl oyed.
Thereafter, this formula CXXXII compound is successively
transformed to the formul a CXXXI I I a~ ~-unsaturated ester and the
10 forTula CXXXIV CBAl intermediate by methods described in Charts J-K
(i.e., the transformation of the formula CXII compound to the
corresponding formula CXIV compounds and the transformation of the
formu1a CXXII compound to the formula CXXIII compound).
Otherwise, the formula VII CBA1 intermediates are prepared
15 according to the method of Chart M, wherein the formula CXLI compound,
prepared above, is reduced to the formula CXLII intermediates by
techniques described in Chart L and references cited therein.
Chart N describes the preparation of the various C~A1 analogs
from the formul a CLI compounds prepared in Charts L and M. Procedures
20 employed in Chart N are those described in Chart F above.
Finally, Chart O provides an alternative method for the prepara-
tion of the formula CLXII C8Al analogs directly from formula CLXI CRA2
analogs. This transformation of Chart O proceeds by direct reduction
of the formula CLXI compound by methods described in Chart M and
25 references cited therein. Chart O i s an especially convenient method
for the preparation of CBA1 analogs wherein Yl is -CH~CH2-.
The formul a XI C8A anal ogs are prepared according to the methods
described in Charts P-U~ With respect to Chart P, the formula CLXXI
compound is known in the art or prepared by methods known in the art.
See United States Patent 4,181,789. This compound is conveniently
transformed to the corresponding formul a CLXXI I methyl ene and formul a
CLXXIII hydroxymethyl compounds by methods known in the art~ Such
procedures are particularly and especially described in United States
Patent 4,012,467 and 4,060,534.
The formula CLXXIII compound thusly prepared is thereaf~er con-
verted to the forlnula CLXXIV mesylate by methods known in the art,
e.g~, reaction with methanesulfonyl chloride in a tertiary amine baseO
Alternatively, other sul fonated derivatives corresponding to the for-
'- 3L~ 71% 3704/3803/3823/3833/3879/3893
-37-
mula CLXXIV co~pound are prepared such as those described in connec-
tion with formula LIII in Chart D.
Thereafter, the formula CLXXIV mesylate (or other sulfonate) is
selectively hydrolyzed to yield the formula CLXXV phenol derivatives.
Selective hydrolysis of R28 silyl ether groups in the presence of
protected Rl8 or M6 hydroxyl groups is accomplished by methods herein-
above described, i.e., the use of tetra-n-butyl ammonium floride by
methods known in the art and hereinabove described. The formula
CLXXV phenol derivative is then cyclized to yield the formula CLXXVI
compounds. Cyclization proceeds most conveniently by treatment of the
formula XVI compound with base at elevated temperaturesJ For example,
n-butyllithium, sodium hydride, or potassium hydride are conveniently
employed at reflux temperatures in organic solvent such as
tetrahydrofuran or glyme.
The cyclized formula CLXXVI compound is then transformed to the
formula CLXXVII compound by ~-carboxyalkylation. Methods known in the
art are employedg e.g., methods for preparing 3,7-inter-phenylene-PGFa
compounds and corresponding phenolic intermediates. For example, the
preparation of the formula CLXXVII compound proceeds by reaction of
the formula CLXXVI compound with sodium hydride and the alkyl bromo-
alkanoate corresponding to the -Z4-COORl group to be introduced into
the molecu1e. Thereafter, the formula CLXXVIII compound is prepared
by deprotection, i.e., hydrolysis under mild acidic conditions of the
protective groups, followed by transformation to various other C-1
derivatives by methods hereinafter described.
Chart Q provides a method whereby further formula XI C~A analogs
in accordance with the present invention are prepared. In particular,
formula XI compounds wherein at least one of R20, R2l, R23, or R24 is
not hydrogen are prepared. In accordance with Chart Q, the formula
30 CLXXXI compound, referred to above in the discussion pertaining to
Chart P, is oxidized to the corresponding formula CLXXXII aldehyde by
methods known in the art. For example, Collins reagent is employed in
this oxidation. When conversion of one C-9 stereoisomer of formula
CLXXXIII to the other is described, refer to the procedure in Chart R.
Thereafter the formula CLXXXII aldehyde is hydrolyzed to the
corresponding formula CLXXXIII phenol derivative by methods described
above for the preparation of the Formula CLXXV compound from the for-
mula CLXXI V compound of Chart P.
L'7 1;~
370~/3803/3823/3833/3879/3893
-38-
Thereafter, cyclization of the formula CLXXXIII to the corres^ponding formula CLXXXIV compound is accomplished by heating at reflux
in an organic solvent the phenoxide anion of the formula CLXXXIII com-
pound. See for reference Casiraghi, G., e~ al., J.C.S. Perkin I, 2027
5 (1979). The C-9 isomers of the formula CLXXXIV compound are conven-
iently separated by conventional techniques, e.g., column chromato-
graphy. Thereafter, the formul a CLXXXIV compound is transformed to
the formula CLXXXV compound by methods described in Chart P for the
preparation of the formul a CLXXVII compound from the formul a CLXXVI
10 compound. This alcohol is then oxidized to the corresponding formula
CLXXXVI ketone (e.g. 3 by methods described above for the preparation
of the formula CLXXXII compound from the formula CLXXXI compound) or
dehydrated to yield the formula CLXXXVIII compound. Such dehydrations
proceed by methods known in the art and incl ude first preparing the
15 mesyl ate coresponding to the fornlul a CLXXXV compound following by
treatment with base.
Thereafter, the formula CLXXXVI or CLXXXVIII compound is trans-
formed, respec~ivelyg to the formula CLXXXVII or CLXXIX compound by
methods hereinafter described.
Fi nally, the formul a CLXXXI X compound thusly prepared i s
dehydrogenated to yield the formula CXC compound by conventional
means, e.g., catalytic dehydrogenation (palladium-on carbon catalyst)
or treatment with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone).
Chart R provides a method whereby the C-9 epimeric forms of com-
25 pounds prepared according to Chart P are prepared. With respect to
Chart R, the formula CXCI aldehyde~ prepared as the formula CLXXXII
compound of Chart Q is isomerized by treatment under basic conditions
(i.e., the use of an organic base such as 1,8-diazobicyclo~5.4.0]-
undec-7-ene in an organic solvent (e.g., methylene chloride)). There-
30 after this 9~-aldehyde is reduced to the corresponding formula CXCIII
alcohol by treatment with a suitable reducing agent, such as a boro-
hydride reducing agent. (e.g., sodium, lithium, or potassium borohy-
dride). Thereafter, the formula CXCIII alcohol thusly prepared is
transformed to the corresponding 9~-CBA analogs by methods described
35 in Chart P, e.g., the transformation of the formula CLXXIII to -the
formul a CLXXVIII compound.
Optionally, the various formula XI CBA analogs prepared accord-
ing to Charts P, Q, and R are prepared by the procedure of Chart S~
~L~ 7.~ 370~/3303/3823/3833/387g/3893
-39-
The procedure of Chart S employs the formula CCI starting materialdescribed in chart P which is thereafter converted to the formula CCII
compound prepared in accordance with methods described for the prepa-
ration of the formula CLXXVIII compound from the formula CLXXI com-
pound of Chart P, the formula CLXXXVII, formula CLXXXIX, formula CXCcompounds from the formula CLXXXI compound of Chart Q and the formula
CXCIV compounds from the formula CXCI compound of Chart R. The for-
mula CCII compound thusly prepared is then transformed to the formula
CCIII compounds by methods hereinabove described, e.g., the transform-
ation of the formula LXXI compound to the formula LXXIII compound ofChart F.
Chart T provides a preferred method whereby the 9-deoxo-2',9-
metheno-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenylene)-PGE1 compounds of
formula CCXIII are prepared. In accordance with Chart T the formula
15 CCXI compound, prepared as the formula CLXXXIII compound of Chart Q,
is treated with a methyl Grignard reagent, methyl magnesium bromide
and heated at reflux in an organic solvent (e.g., glyme).
The formula CCXII thusly prepared is then transformed to the
formula CCXIII product by the method described in Chart P for the
preparation of the formula CLXXVIII product from the formula CLXXVI
phenol intermediate.
Chart U provides a convenient method whereby formula XI compounds
wherein Y1 is trans-CH=CH-, the formula CCXXI compound oF Chart U, are
transformed to corresponding formula CCXXII aldehyde intermediates.
This trans~ormation is accomplished by ozonolysis by methods otherwise
known in the art.
The formula CCXXII intermediate is then conveniently transformed
to various formula XI products (the Formula CCXXIII compound of Chart
U) by methods described above, i.e., reaction of the formula CCXXI ~
compound with the appropriate Wittig reagent ~ollowed by reduction and
hyqrolysis. Accordingly by the procedure described in Chart U the
C-12 side chains of the various formula CCXXI compounds is conven-
iently modified by the formula CCXXII aldehyde intermediates.
As discussed above, the processes herein described lead variously to
carboxylic acids (X1 is -COOR1 and R1 is hydrogen) or to esters or
primary alcohols (X1 is -CH20H).
When the alkyl ester has been obtained and an acid is desired,
saponification procedures, as known in the art for PGF-type compounds
3~i2 3704/3803/3823/3833/387g/3893
-40 -
are employed.
When an acid has been prepared and an alkyl, cycloalkyl, oraralkyl ester is desired9 esterification is advantageously
accomplished by interaction of the acid with appropriate
diazohydrocarbon. For example, when diazomethane is used, ~he methyl
ester is produced. Similar use of diazoethane, diazobutane, and
1-diazo-2-ethylhexane, and diazodecane, ~or example, gives the ethyl,
butyl, and 2-ethylhexyl and decyl esters, respectively. Similarly,
diazocyclohexane and phenyldiazomethane yield cyclohexyl and benzyl
esters, respectively.
Esterification with diazohydrocarbons is carried out by mixing a
solution of the diazohydrocarbon in a suitable inert solvent,
preferably diethyl ether, with the acid reactant, advantageously in
the same or a different inert diluent. After the esterification
reaction is complete the solvent is removed by evaporation, and the
ester purified if desired by conventional methods, preferably by
chromatography. It is preferred that contact of the acid reactants
with the diazohydrocarbon be no longer than necessary to effect the
desired esterification, preferably about one to about 1n min, to avoid
undesired molecular changes. Diazohydrocarbons are known in the art
or can be prepared by methods known in the art. See, for example,
Organic Reactions, John Wiley and Sons, Inc., New York, N.Y., Vol. 8,
pp. 38g-394 (1954).
An alternative method for alkyl, cycloalkyl or aralkyl
esterification of the carboxy moiety of the acid compounds comprises
transformation of the free acid to the corresponding substituted
ammonium salt, followed by interaction of that salt with an alkyl
iodide. Examples of suitable iodides are methyl iodide, ethyl iodide,
butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide,
cyclopentyl iodide, benzyl iodide, phenethyl iodide, and the like.
Various methods are available for~ preparing phenyl or substituted
phenyl esters within the scope of the invention from corresponding
aromatic alcohols and the free acidg differing as to yield and purity
of product.
With regard to the preparation of the phenyl, particularly
p-substituted phenyl esters disclosed herein (i.e., Xl is -COOR1 and
R1 is p-substituted phenyl), such compounds are prepared by the method
described in U.S. Patent No. 3,890,372~ Accordingly3 by the preferred
7~1~ 3704/3803/3823/3~33/3879/3893
-~1
method described therein, the p-substituted phenyl ester is prepared
first by forming a mixed anhydride, particularly fol10wing the
procedures described below for preparing such anhydrides as the first
step in the prepara~ion of amido and cycloamido derivatives~
This anhydride is then reacted with a sol ution of the phenol
corresponding to the p-substituted phenyl ester to be prepared. This
reaction proceeds preferably in the presence of a tertiary amine9 such
as pyridine. When the conversion is complete, the p-substituted
phenyl ester has been recovered by conventional techniques.
A preferred method for substituted phenyl esters i s that
disclosed in U.S. Patent NoO 398909372 in which a mixed anhydride is
reacted with an appropriate phenol or naphthol. The anhydride is
formed from the acid with isobutyl chl oroformate in the presence of a
tertiary amine.
Phenacyl type esters are prepared from the acid using a phenacyl
bromide, for example p-phenyl phenacyl bromide, in the presence of a
tertiary amine. See9 for example, U~S~ Patent No. 3,984,454, German
Offenlegungsschrift 2,535,693, and Derwent Farmdoc No. 16828X.
Carboxyamides (Xl is -C0~4) are prepared by one of several
20 amidation methods known in the prior art. See, for examp~e, U.S.
Patent No. 3,981,868, issued 21 September 1976 for a description of
the preparation of the present amido and cycloamido derivatives of
prostaglandin-type free acids and U.S. Patent No. 3,954,741 describing
the preparation of carbonyl amido and sul fonyl amido derivatives of
25 prostaglandin-type free acids~
The preferred method by which the present amido and cycloamido
derivatives of the acids are prepared is, first, by transformation of
such free acids to corresponding mixed acid anhydrides. ~y this
procedure, the prostaglandin-type free acid is first neutralized with
30 an equivalent of an amine baseg and thereafter reacted with a slight
stoichiometric excess of a chloroformate corresponding to the mixed
anhydride to be prepared.
The amine base preferred for neutralization is triethylamine,
although other amines (e.g., pyridine, methyldiethylamine) are
35 likewise employed. Further, a convenient3 readily available
chl oroformate for use in the mixed anhydride production is isobuty1
chl oroformate.
The mixed anhydride formation proceeds by conventional methods
` 3L~q~ 7~ 370~/3803/3823/3833/3879/3893
-42-
and accordingly the free acid is mixed with both the tertiary amine
base and the chloroformate in a suitable solvent (e.g., aqueous
tetrahydrofuran), allowing the reaction to proceed at -10C to 20C.
Thereafter, the mixed anhydride is converted to the corresponding
amido or cycloamido derivatives by reaction with the amine corres-
ponding to the amide to be prepared. In the case where the simple
amide (-NH2~ is to be prepared9 the transformation proceeds by the
addition of ammonia. Accordingly, the corresponding amine (or
ammonia) is mixed with the mixed anhydride at or about -10 to +10Cg
until the reaction is shown to be complete.
Thereafter, the novel amido or cycloamido derivative is recovered
from the reaction mixture by conventional techniques.
The carbonylamido and sulfonylamido derivative of the presently
disclosed PG-type compounds are likewise prepared by known methods.
See, for example, U.S. Patent No. 3,954,741 for description of the
methods by which such derivatives are prepared. ~y ~his known rnethod
the acid is reacted with a carboxyacyl or sulfonyl isocyanate, corres-
ponding to the carbonylamido or sulfonylamido derivative to be pre-
paredO
By another, more preferred method the sulfonylamido derivatives
of the present compounds are prepared by first generating the PG-type
mixed anhydride, employing the method described above for the prepar-
ation of the amido and cycloamido derivatives. Thereafter, the sodium
salt of the corresponding sulfonamide is reacted with the mixed anhy-
dride and hexamethylphosphoramide. The pure PG-type sulfonylamido
derivative is then obtained from the resulting reaction mixture by
conventional techniques.
The sodium salt of the sulfonamide corresponding to the
sulfonylamido derivative to he prepared is generated by reacting the
sulfonamide with alcoholic sodium methoxide. Thus, by a preferred
method methanolic sodium methoxide is reacted with an equal molar
amount of the sulfonamide. The sulfonamide salt is then reacted, as
described above, with the mixed anhydride, using about four
equivalents of the sodium salt per equivalent of anhydride. Reaction
temperatures at or about 0C are employed.
The compounds of this invention prepared by the processes of this
invention, in free acid form, are transformed to pharmacologically
acceptable salts by neutralization with appropriate amounts of the
7:~2 3704/3803/3823/3833/3879/3893
-43-
corresponding inorganic or organic base, examples of which correspond
to the cations and amines listed hereinabove. These transformations
are carried out by a variety of procedures known in the art to be
generally useful for the preparation of inorganic, i.e., metal or
5 arrunonium salts. The choice of procedure depends in part upon the
solubility characteristics of the particular salt to be prepared. in
the case of the inorganic salts, it is usually suitable to dissolve an
acid of this invention in water containing the stoichiometric amount
of a hydroxide, carbonate, or bicarbonate corresponding to the
10 inorganic salt desired. For example, such use of sodium hydroxide,
sodium carbonate, or sodium bicarbonate gives a solution of the sodium
salt. Evapora~ion of the water or addition of a water-miscible
solvent of moderate pol arity, for example, a lower al kanol or a lower
alkanone, gives the solid inorganic salt if that form is desired.
To produce an amine salt, an acid of this invention is dissolved
in a suitable solvent of either moderate or low polarity. Examples of
the former are ethanol, acetone, and ethyl acetate. Examples of the
latter are diethyl ether and benzene. At least a stoichiometric
amount of the amine corresponding to the desired cation is then added
20 to that solution, If the resulting salt does not precipitate, it is
usually obtained in solid form by evaporation. If the amine is
rel atively vol atil e, any excess can easily be removed by evaporation.
It is preferred to use stoichiometric amounts of the less volatile
amines.
Salts wherein the cation is quaternary ammonium are produced by
mixing an acid of this invention with the stoichiometric amount of the
corresponding quaternary ammonium hydroxide in water solution,
followed by evaporation of the water.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is more completely understood by the
operation of the following examples:
Example 1 3-oxo-7c.-tetrahydropyran-2-yl oxy-6~ (3 'S )-3'-tetra-
hydropyran-2-yl oxy-trans l'-octenyl ]-bicycl o[3. 3, 0~-
oct-1-ene (Formula XXIV: R18 is tetrahydropyranyloxy;
Y1 is trans-CH-CH-, M6 is a-tetrahydropyranyloxy:3-H~
Ll is c~-H:~-H, R27 is n-butyl; and n is the integer
one).
Refer to Chart A.
t7 1~ 3704/3803/3823/3833/3879/3893
-4~
A. To a stirred solution of 19 ml (170 mmoles) dimethyl methyl-
phosphonate and 600 ml of dry ketrahydrofuran at -78C under an argon
atmosphere is added dropwise over 5 min 110 ml (172 mmoles) of 1.56 M
n-butyllithium in hexane. The resulting solution is stirred for 30
5 min at -78C, treated with 25~4 9 of 3a,5a-dihydroxy-2~-(3a-hydroxy-
trans-l-octenyl)-la-cyclopentaneacetic acid, lactone, bis~tetrahydro-
pyranyl)ether, in 100 ml of dry tetrahydrofuran dropwise over one hr,
and stirred for one hr at -78C and four hr at room temperature~ The
reaction is then quenched by addition of 10 ml glacial acetic acid,
10 diluted with 700 ml of brine, and extracted with die~hyl e~her (3 x
700 ml). The combined ethereal layers are washed with 200 ml bicarb
and 500 ml brine and dried over anhydrous sodium sulfate and concen
trated under reduced pressure to yield 37 9 of formula XXII compound
as oily white solid: 3-dimethyl phosphonomethyl-3-hydroxy-2-oxa-7-
15 tetrahydropyran-2-yl oxy-6~(3'S)-3'-tetrahydropyran-2-yl oxy-trans-1 '-
octenyl l-bicYcloC3.3.0]octane. Crystallization of the crude product
from hexane and ether yiel ds 22.1 9 of purified formul a XXII product.
Silica gel TLC Rf is 0.22 in ethyl acetate. The melting range is
89-93C. NMR absorptions are observed at 3.72 (doublet, J=llHz) and
20 3.83 (doublet, J=llHz)~. Characteristic infrared absorptions are
3340, 1250, 1185, 1130, 1075, and 1030 cm .
B. To a solution of lOoO g of the product of Part A in 75 ml
acetone stirring under a nitrogen atmosphere at -10C is added over 3~
min 9.0 ml of Jones reagent. The resulting suspension is s~irred for
25 30 min at -10C and then quenched with 4 ml 2-propanol. The solvents
are decanted away from the green residue and most of the acetone
removed at reduced pressure. The acetone concentrate is then taken up
in ethyl acetate and washed with saturated aqueous sodium bicarbonate
and then with brine and dried over anhydrous sodium sul fate. Concen-
30 tration under reduced pressure yields 8.2 9 of formula XXIII product:2-decarboxy~6-desbutyl-6-dilnethyl phosphonomethyl-6-keto-PGEl, 11,15-
bis(tetrahydropyranyl ether). Chrornatography of formula XXIII product
on 600 9 silica gel eluting with 20% acetone in methylene chloride
yields 4.95 9 of pure formula XXIII product~ Sil ica gel TLC Rf (in
35 20% acetone in methylene chloride) is 0.22. Characteristic NMR
absorptions are observed at 3.14 (doublet, J=23 Hz) and 3.80 (doublet,
J=11 Hz), 5.4-5.8 (m)~. Characteristic infrared absorptions are
observed at 1745, 1715, 1260, 1200, 1185, 11309 1030, 97n, 87n cm .
~2~12
3704/3803/3823/3833/3879/3893
-45-
C. A suspension of 5.37 g of the product of Example 1, Part B,1.33 9 anhydrous potassium carbonate9 and 5.37 g 18-Crown-6 ether in
200 ml tol uene is heated at 75C for six hr under a nitrogen atmos-
phere, cooled to 0C, and washed with 200 ml brine, 200 ml of 3:1
5 water:brine, and 200 ml brine, and dried over anhydrous sodium
sul fate. Most of the solvents are removed under reduced pressure and
the residue is filtered through 50 g silica gel eluting with 250 ml
ethyl acetate to give 3.9 g of formula XXIV product: 3-oxo-7a-tetra-
hydropyranyl -2-yl oxy-6~C(3 'S )-3 '-tetrahydropyran-2-yl -trans-1 '-
octenyl~bicyc10~3.390~oct-1-ene. The crude product is chrornatographed
on 300 9 silica gel eluting with 60:40 hexane:ethyl acetate to give
2.39 g of pure title product. Silica gel TLC Rf is 0.22 in 60:40
hexane:ethyl acetate. IIMR absorptions are observed at 5.18-5.86 (m)
and 5.94 (broad singlet)~. Infrared absorptions are observed at 1710
and 1632 cm~ .
Following the procedure of Example 1, but employing the various
3a~5~-hydroxy-2~substituted-1-cyclopentaneacetic acid ~-lactones of
formula XXI, there are prepared each of the various corresponding
formula XXIV products wherein n is one~
Further, following the procedure of Example 1, but employing each
of the various 3a,5-dihydroxy-2-substituted-1O~-cyclopentanepriopionic
acid, 3-lactones of formul a XXI, there are prepared each of the
various formula XXIV compounds wherein n is 2.
Further, following the procedure of Example 1, but enlploying each
25 of the various 5-hydroxy-2-substituted-1~-cyclopentaneal kanoic acid
lactones of formul a XXI, there are prepared each of the various
formula XXIV compounds wherein R1a is hydrogen. Finally, following
the procedure of Example 1, but emp`loying each of the various 3~-
hydroxymethyl-5~ hydroxy-2-substituted-1a-cyclopentaneal kanoic acid
30 l actones of formul a XXI, there are prepared each of the various
formula XXIV compounds wherein Rl8 is -CH20RIo.
Example 2 3-oxo-8~-tetrahydropyran-2-yloxy-7~[(3 'S)-3 '-tetrahy-
dropyran-2 -yl oxy-trans-l'-octenyl]bicycl o~4.3.0]non-1-
ene (Formula XXIV: Rl8~ Y1, M6, R7 are defined in
Example 1 and n is the integer 2).
Refer to Chart A.
A. A solution of 2.05 ml (18.9 mmoles) of dimethyl methylphos-
phonate and 100 ml of dry tetrahydrofuran is stirred a~ -78C under a
- ~Z~?~IL'71;2 3704/3803/3~23/3~33/3879/~893
-46 -
nitrogen atmosphere and treated dropwise with 11.8 ml (18.9 mmoles~ of
1.6 molar n-butyllithium in hexane. A~ter stirring for 30 min at
-78C, the resulting mixture is treated dropwise over 25 min with 4.25
g of 3,5a-dihydroxy-2~-(3~-hydroxy-trans-1-octenyl) 1~-cyclopentane
5 propionic acid~ ~-lactone, 11,15-bis(tetrahydropyranyl ether), in 30
ml af dry tetrahydrofuran. The resulting mixture is then stirred for
one hr at 78C~ The solution is then allowed to stir at ambient
temperature for 2 hr and is quenched by addi~ion of 1.2 ml of acetic
acid. The mixture is then added to ~50 ml of brine and 200 ml of
10 diethyl ether. The aqueous and organic layers are then separated and
the aqueous layer extracted twice with diethyl ether. The ethereal
extracts are then washed with brine, dried over anhydrous sodium
sulfate, and concentrated to yield 5.6 9 of crude formula XXII com-
pound, as an oil: 3-(dimethyl phosphonomethyl)-3-hydroxy-2-oxa-8~-
15 tetra-hydropyran-2-yl-oxy-7~[(3'5)-3'-tetrahydropyran-2~yl oxy-transl'-
octenyl]-bicyclo[4.3.0]nonane~ Chromatography on silica gel eluting
with 4:1 ethyl acetate:acetone yields 4~1 9 of purified formula XXII
product. Characteristic NMR absorption is observed at 5.15-5.65
(multiplet)~. Silica gel TLC Rf is 0.34 in 4:1 ethyl acetate:acetone.
20 Characteristic infrared absorptions are observed at 3350, 1235, and
1030 cm~ .
B. A suspension of 3.42 9 of chromium trioxide and 80 ml of
methylene chloride is treated with 5.8 ml of pyridine, stirred at
ambient temperature under a nitrogen atmosphere for 30 min, and
25 combined with 3 scoops of dry diatomaceous earth. The resulting
mixture is then treated with 3.25 9 of the reaction product of Part A
and 8 ml of dry dichloromethane, stirred for 30 min at ambient
temperature under nitrogen, filtered through 30 9 of silica gel
(eluting with 2û0 ml of ethylacetate and acetone, 2:1) and concen-
30 trated under reduced pressure. Chromatographing the residue (3.73 9)on 120 9 oF silica gel, eluting with ethyl acetate and acetone (4:1)
yields 2.07 9 of formul a XXIII product: 2-decarboxy-S-despropyl-6-
dimethylphosphonomethyl-5-keto-PGEl, 11,15-bis(tetrahydropyranyl
ether). Characteristic infrared absorptions are observed at 17~0 and
35 1715 cm .
Characteristic NMR absorptions are observed at 301 (doublet, J-23
Hz) and 3.8 (doublet, J=ll Hz~.
C. A suspension of 12 mg of 50qo sodium hydride in mineral oil
3704/3803/3~23/3833/3879/3893
-47-
and 3 ml o~ diglyme is stirred at 0O. under an argon atmosphere. Thesuspension is then treated wi~h 150 mg of the product of Part B in 3
ml of diglyme. After 1 hrs the cooling bath is removed and the
resulting solution is stirred at ambient temperature under argon.
After a total of 20 hr from addition of the Formula XXIII reactant,
the resulting solution is then added to 30 ml of water and extracted
with 90 ml of diethyl ether. The ethereal extract is washed with
brine (30 ml), dried over anhydrous sodium sulfate, concentrated under
reduced pressure to a brown oil (110 mg) and chromatographed on 10 9
of silica gel eluting with hexane and e~hyl acetate (1-1). There is
accordingly prepared 15 mg of formula XXIV compound: 3-oxo~8~-tetra-
hydropyran-2-yloxy-7~-[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-
octenyl]bicyclo~4.3.0]nun-1-ene. NMR absorptions are observed at 4.7
(broad singlet) and 5.3-6.0 (multiplet~. IR absorption is observed
at 1670 cm~ .
Alternatively, the formu1a XXIV compound above is prepared as
follows:
A solution of 150 mg of the product of Part B and 5 ml of dry
tetrahydrofuran at 0C under an argon atmosphere is treated dropwise
with 0.5 ml of 0.52 M potassium hydride and 18-crown-6 ether (Aldrich
Chemical Co. Catalog Handbook of Fine Chemicals 1979-1980, Milwaukee,
Wisconsin, p. 133; Pedersen, J.C., JACS 92:386 (1970)) in tetra-
hydrofuran (prepared from 800 mg potassium hydride and 1.0 g 18-
crown-6 ether in 8.7 ml of dry tetrahydrofuran). After stirrin~ for
one hr at 0C under argon, the mixture is added to 30 ml of water,
extracted with 90 mg of diethyl ether and the ethereal extract is
washed with brine, dried over anhydrous sodium sulfate, concentrated
under reduced pressure, and chromatographed on 9 9 o~ slica gel elut-
ing with ethyl acetate and hexane. Formula XXIV product (40 mg) is
thereby obtained. Silica gel TLC Rf is 0.30 in ethyl acetate and
hexane (1:1).
Example 3 1~-Methyl-3-oxo-7~-tetrahydropyran-2-yl-oxy-6~-
~(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl~-
bicyclo-~3.3.0]octane (Formula XXV: Rl89 Yl, ~6, n, Ll,
R7 are as defined in Example 1, Rl6 is hydrogen and R~7
is methyl).
Refer to Chart A.
A suspension of 2.70 9 of anhydrous copper iodide is stirred in
3704/3803/3823/3833/3879/3893
-48-
100 m1 of anhydrous diethyl e~her at -20C under an argon atmosphere
and is treated dropwise wi~h 20.0 ml of 1~4 M ethereal methyllithium.
The resulting solution is then stirred for 15 min at -20C and treated
over 2.5 hr at 20C with a solution of 2.00 g of the title product of
Example 1 in 100 ml o~ anhydrous diethyl ether. S~irring is continued
for an additional 1.5 hr at -20C and the resulting mixture added to
200 ml of 1 M aqueous ammonium chloride. The aqueous and organic
layers are then separated and the aqueous layer extracted with
diethylether (400 ml). The combined organic extracts are then washed
with 200 ml of brine, dried over anhydrous sodium sulfate, concen-
trated under reduced pressure to yiel d 2.4 9 of title product as a
pale green oil. Chromatography on 25 9 of silica gel eluting with
hexane in ethyl acetate (3:1) yields 2.0 9 of title product as a
colorless oil. Characteristic NMR absorptions (CDCl3) are observed at
1.18, 3.20-4.43~ 4.70, and 5.2-5~9~. Characteristic infrared absorp-
tions are observed at 1745, 1665, 1200, 1130, 1110, 1075, 1035, 1020,
980, and 870 cm . Silica gel Rf is 0.26 in ethyl acetate and hexane
(1 3).
By procedures known in the art, each of the various novel formula
XXV intermediates is transformed to a 9~-methyl-C8A2 or C3A1 compound
by methods examplified hereinafter or known from ~ritish Published
Specifications 2,013,661, 2,014,143, and 2,017,699.
Example 4 5-Carboxypentanol, t-butyldimethylsilyl ether
A solution of 4 9 of sodium hydroxide in 100 ml of methanol and
water (4:1) is treated with 10 ml of caprolactone and stirred at
ambient temperature under a nitrogen atmosphere. After 2n hr, solvent
is evaporated following addition of toluene, yielding 15 9 of solid,
crude 5-carboxypentanol.
The above solid is suspended in 300 ml of dimethylformamide und~r
a nitrogen atmosphere, cooled to ~C, treated with 35 9 of imidazole,
stirred for 15 min at 0C and 15 min at ambient temperature, cooled to
0C and treated with 39 g of t-butyldimethyl silylchloride. The
resulting solution is then allowed to warm to ambient temperature
under a nitrogen atmosphere. After 26 hr, the resulting solution is
treated with 8 9 of sodium hydroxide ln 40 ml of water and 40 ml of
methanol, with stirring maintained under a nitrogen atmosphere. After
13 hr, the suspension is acidified to pH 4 with 500 ml of 1 N aqueous
hydrogen chloride, then saturated with sodium chloride and extracted
'7:~
` 3704/3803/3823/3833/387g/3893
-49-
with ethyl acetate. The ethyl acetate extracts are then washed with 1
N aqueous sodium hydroxide~ The basic extracts are then acidified to
pH 4 with concentrated hydrochl~ric acidg saturated with brine, and
extracted with ethyl acetate. The ethyl acetate extracts are then
washcd with brine, dried over sodium sulfate~ and concentrated under
reduced pressure to yield 2206 g of a yellow liquid, 5-carboxy-
pentanol, t-butyldimethylsilyl ether. Chromatography on 800 g of
silica gel eluting with ethyl acetate and hexane (1:9 to 1:1) yields
14.8 g of 5 carboxypentanol, t-butyldimethylsilyl ether. NMR
absorp~ions are observed at 0.05 (singlet) and 0.90 (singlet)~
Infrared absorptions are observed at 3000 (broad3 and 1700 cm
Following the procedure of Example 4, but employing each of the
various lactones corresponding to the ~-carboxyalkanol compounds of
formula XXXII there are prepared each of the various formula XXXII
products.
Example 5 2-Decarboxy-2-(t-butyldimethyl 5i 1 yl oxy) methyl-5-car-
boxy-6-hydroxy-9~-methyl-CBA1, 11,15-bis(tetrahydro-
pyran)ether (Formula XXXIII: R28 is t-butyldimethyl-
silyl~ Z2 iS -(CH2)3-, n is 1, and R16, Rl8, R37~ M6,
L1, and R4 are as defined in Example 3).
Refer to Chart B.
A solution of 0.58 ml of dry diisopropylamine and 20 ml of dry
tetrahydrofuran at 0C under an argon atmosphere is treated with 2.6
ml of 1.56 M n-butyl1ithium in hexane, stirred for 5 to 10 min at 0C,
treated with 0.50 g of the title product of Example 4 in 5 ml of
tetrahydrofuran, stirred for 15 min at 0C and 1 hr at ambient
temperature, cooled to O~C, treated with 0.91 9 of the title product
o~ Example 3 in 5 ml of tetrahydrofuran, and allowed to slowly warm to
ambient temperature under an argon atmosphere. - Thereafter, 130 ml of
water and 20 ml of brine are added and the mixture extracted with
diethyl ether. The ethereal extracts are then washed with 4 ml of 1 N
aqueous hydrochloric acid and 150 ml of brine and dried over sodium
sulfate, and concentrated under reduced pressure to yield title
product.
Following the procedure of Example 5, but employing each of the
various formula XXXI compounds described
following Example 1, there are prepared each of the various formula
XXXIII compounds wherein R28 is t-butyldimethylsilyl and Z2 is
712
-`~ 3704/3803/3823/3833/3879/3893
-50-
-(CH2)3--
Example 6 2-Decarboxy-2-(t-bu~yldimethylsilyloxy)methyl-9~-
~ethyl-GBA2~ 11,15-bis-(tetrahydropyranylether)
(Formula XXXIV: 22a~ Z2~ n, R18, Y1, M6, L1 and R7 are
as defined for Examples 1 and 5).
The reaction product of Example 5 (1.37 g) and 16 ml of methylene
chloride is treated with 2.9 ml of dimethylformamide dineopentyl
acetal, stirred for 3 hr at ambient temperature under nitrogen, added
to 160 ml of ice water and 40 ml of brine, and extracted with diethyl
ether. The ethereal extracts are then washed with 150 ml of sodium
bicarbonate and 150 ml of brine, dried over sodium sulfate, and
concentrated under reduced pressure to yie1d crude title product.
Chromatography on 100 9 of silica gel eluting with 10% ethyl acetate
in hexane yields pure title product.
Following the procedure of Example 6, but employing each of the
various formula XXXIII compounds described following Example 5~ ~here
are prepared each of the various corresponding formula XXXIV products
wherein R28 is t-butyldimethylsilyl and Z2 is -~CH2)3-. .
Example 7 2-Decarhoxy-2-hydroxymethyl-9~-methyl-CBA2, 11,15-
bis(tetrahydropyranyl~ether (Formula XXXV: Z2, n, R16,
R37, R1S~ Y1, M69 L1~ and R7 are as defined in Examples
1 and 5).
Refer to Chart B.
A solution of 0~71 9 of the title product of Example 6 and 16 ml
of dry tetrahydrofuran at 0C under a nitrogen atmosphere is treated
with 3.2 ml of 0.75 molar tetra-n-butylammoniumfluoride and tetrahy-
drofuran. After allowing the reaction mixture to slowly warm to
ambient temperature overnight with stirring, 150 ml of brine is added
and the resulting mixture extracted with ethyl acetate. The ethyl
acetate extracts are then washed with 0.5 N aqueous po-tassium
bisulfate, 100 ml of sodium bicarbonate, and 100 ml of brine, dried
ovér sodium sulfate, and concentrated under reduced pressure to yield
crude title product. Filtering through 25 9 of silica gel with 200 ml
of ethyl acetate and hexane yields 0.61 g of further purified product.
3S Chromatography on silica gel eluting with 35% ethyl acetate in hexane
yields pure title product.
Following the procedure of Example 7~ but employing each of the
various formula XXXIV compounds described in and following Example 6,
7~LZ 370~/3803/3823/3833/387g/3893
-51-
there are prepared each of the various formula XXXV compounds whereinZ2 is -(CH2)3--
Following the procedure of Examples 5, 6, and 73 and employingthe various starting materials described in and fol1Owing these
examples and each of the various ~ormula XXXII compounds described in
and following Example 4, there are prepared each of the various
formula XXXV compounds.
Example 8 2-Dccarboxy-2-hydroxymethyl-9~-methyl-CBA2 ( Fo rmul a
XXXVI: Xl is -CH20H, Z2 is -~CH2)3-, R8 is hydroxy, Y1
is trans-CH=CH-~ Ml is a-OH:~-H, Ll is ~-H:~-H and R7
is n-butyl).
Refer to Chart B.
The title product of Example 7 (0.25 9) is combined with 9 ml of
acetic acid, water and tetrahydrofuran (6:3:1) and heated to 37-40C
for two hr. Thereafter the resulting mixture is cooled and extracted
with diethyl ether. The ethereal extracts are then washed with brine,
dried over sodlum sulfate and concentrated to yield crude title pro-
duct. Chromatography on silica gel yields pure title product.
Following the procedure of Example 7, but employing each of the
various formula XXXV primary alcohols described in and following
Evample 7 there are prepared each of the various corresponding formula
XXXVI products wherein Xl is -CH20H.
Example 9 o-(t-Butyldimethylsilyloxyethyl)benzaldehyde (Formula
XLIV: R28 is t-butyldimethylsilyloxy and 9 is one).
Refer to Chart C.
A. To a mixture of 7.6 9 of lithium aluminum hydride and 400 ml
of dry tetrahydrofuran under a nitrogen atmosphere is added dropwise
with stirring 18 g of homophthalic acid (Aldrich Chemical Company) in
250 ml of dry tetrahydrofuran. Dropwise addition rate is adjusted
such that mild reflux is maintained during the course of the
exothermic reaction. The resulting mixture is then heated at reflux
for 5 hr, cooled to 0C, and 7.6 g of water in 50 ml of tetrahydro-
furan is added dropwise with stirring. Thereafter 27 ml of 10
aqueous sodium hydroxide is added and the resulting mixture is stirred
at ambient temperature for 20 min, filtered, and the filter solids
washed with 150 ml of tetrahydrofuran. The filtrate and tetrahydro-
furan wash are then concentrated under reduced pressure to yield 14~0
g of crude formula XXXII diol, 2-(o-hydroxymethylphenyl~ethanol.
- 3L~ 3704/3803/3823/3833/3879/3893
-52-
Chromatography on 1~2 kg of silica gel, deactivated by addition of 240
ml of ethyl acetate, eluting with ethyl acetate, yields 13~5 g of
formula XLII product. Melting range is 41.5-43C.
Bo To a solution of 130 5 9 of the reaction product of Part A in
50 ml of dry tetrahydrofuran under a nitrogen atmosphere is added with
stirring 9.05 9 of imidazole. The resulting solution is then cooled
to -5C and 13.9 9 of t-butyldimethylsilyl chloride is added. The
resulting mixture is then maintained for 20 min and thereafter allowed
to warm to ambient temperature. After 1 hr~ the resulting mixture is
then shaken with 500 ml sf hexane and diethylether (2:1) and 250 ml of
water and brine (1:1). The organic layer is then washed witn water
and brine, dried over magnesium sulfate, and concentrated under re-
duced pressure to yield a crude mixture of mono- and bis-silyl ethers
corresponding to the starting material of Part A. This mixture of
products is then chromatographed on 2 kg of silica gel, deactivated
with 400 ml of ethyl acetate and eluted wi~h 2570 ethyl acetate and
Skellysolve B to yield 6.82 g of formula XLIII product, o-(t butyl-
dimethylsilyloxyethyl)phenylmethanol. NMR absorptions are observed at
7.20-7.52, 4.57, 3.91 (t, J Gol)~ 2~93 (t~ J 6.1), 0.82, and -0008~.
Silica gel TLC R~ is 0.54 in 25% ethyl acetate and hexane.
C. A mixture of 5.0 9 of the reaction product of Part R, 100 ml
of trichloromethane, and ~5 9 of activated manganese dioxide (MnO2) is
stirred at ambient temperature for 4 hr. Chloroform (100 ml) is then
added and the resulting mixture filtered through diatomaceous earth.
After washing filter solids with 200 ml of trichloromethane, the re-
sulting filtrate and wash is then concentrated under reduced pressure
to yield a residue containing title products Chromatography on 400 g
of silica gel, deactivated with 80 ml of ethyl acetate and elution
with 25% ethyl acetate and hexane yields 2.93 9 of pure title product.
Silica gel TLC R~ i s 0. 74 in ~5% ethyl acetate and hexane. NMR
absorptions are observed at 10.34, 7.25-8.00~ 3.89 (t, J 6.0), 3.27
(t, J 6.0), 0.83 and -0.09~. The mass spectrum exhibits a peak at 265
(M+1) and other peaks of decreasing intensity at m/e 75, 207, 73, 133,
223, 208, 77, 177, 76 and 105.
Following the procedure described in Chart C, but employing each
of the various formula XXXI acids, there is prepared each of the
various corresponding formula XXXIV aldehydes ~herein R2S is t-butyl-
dimethylsilyl.
3704/38~3/3823/3833/3879/3893
-53-
Example 10 m-(t-butyldimethylsilyloxymethyl)benzaldehyde (Formula
XLIV: g is zero and R28 is t-butyldimethylsilyl).
Refer to Chart C.
A. To a solution of lOoO g of m-(hydroxymethyl)phenylmethanol in
5 40 ml of dry tetrahydrofuran under a nitrogen atmosphere is added with
stirring 7.35 9 imidazole. The resulting solution is then cooled to
0C and 11,3 9 of t-butyldimethylsilyl is added~ The resulting mix-
ture is then stirred with cooling for 15 min and thereafter allowed to
warm to ambient temperature. After 90 min9 the resulting mixture is
10 then shaken in 400 ml of hexane and diethyl ether (2:1) and 200 ml of
water and brine (1:1). The organic layer is then washed successively
with water and brine (1:1, 30û ml) and brine ~150 m1), dried over mag-
nesium sulfate and concentrated under reduced pressure to yield a mix-
ture of mono- and bis-t-butyldimethylsilyloxy ether corresponding to
15 the formula XXXII compound. This mixture of products is then chroma-
tographed on 1,4 kg of silica gel, deactivated by addition of 280 ml
of ethyl acetate and el uted with 25-40~o ethyl acetate in hexane to
yield 7.65 9 of pure formula XLIII product, m-(t-butyldimethylsilyl^
oxymethyl)phenylmethanol. Silica gel TLC R~ is 0.46 in 257O ethyl
20 acetate and hexane. NMR absorptions are observed at 7.25, 4.72, 4.60,
2.23, 0.92, and 0.09~. The mass spectrum exhibits a peak at 251
(M :1) and other peaks of decreasing intensity at m/e 235, 121, 195,
237, 105, 133, 75, 89, 236, and 119.
B~ A mixture of 5.0 g o~ the reaction product of Part A and 100
25 ml of trichloromethane and 25 9 of activated manganese dioxide tMn02)
is stirred at ambient temperature for 4 hr. Chl oro-form (100 ml) is
then added and the resulting mixture filtered through diatomaceous
earth. The filter solids are washed with 200 ml of trichloromethane
and the filtrate and trichloromethane wash are then concentrated under
30 reduced pressure to yield 5~2 9 of crude title product. Chromato-
graphy on 400 9 of silica gel, deactivated with 80 ml of ethy1 acetate
and elution with ethyl acetate and hexane (1:3) yields 3.65 9 of pure
title product. Silica gel TLC Rf is 0.46 in 10X ethyl acetate and
hexane~ NMR absorptions are observed at 10.00, 7.26-7.86, 4.81, 0.95,
35 and OolllS~
Example 11 3-Phenyl sul fonyl-7a-tetrahydropyran-2-yl oxy-6 B- C~3 'S ~-
3 '-tetrahydropyran-2-yl oxy-trans-1'-octenyl~ bicycl o-
[3.3.0]octane (Formula LV: n is the integer one3 R18
~ L~ L~2 3704/3803/3823/3833/3879/3893
-5~-
is tetrahydropyr~nyloxy, Y1 is trans-CH=CH-~ M6 is
a- tetrahydropyranyloxy:~-hydrogen, Ll is -hydrogen:
~-hydrogen~ R16 and R17 are both hydrogeng and R27 is
n-butyl).
Refer to Chart D.
A. Sodium borohydride (0.38 g) is added with stirring to a
solution of 2.90 9 of 3-oxo-7a-tetrahydropyran-2-yloxy-6~-~(3'S)-3'-
tetrahydropyran~2-yloxy-trans-1'-octenyl]-bicyclo~3.3.0~octane in 25
ml of 95% aqueous et'hanol. The resulting mixture is then stirred at
ambient temperature for 20 min. Thereafter the resulting mixture is
shaken in 100 ml of brine and 200 ml of ethyl acetate. The organic
layer is then immediately washed in brine~ dried over magnesium
sulfate~ and concentrated under reduced pressure to yield 2.94 9 of
formula LII alcohol: (3RS)-3-hydroxy-7a-tetrahydropyran-2-yloxy 6~-
~(3'S)-3'-tetrahydropyran-2-yloxy-trans~ octenyl]bicyclo~3.3.0]-
octane. Infrared absorptions are observed at 3600 and 3450 cm~ and
no carbonyl absorption. Silica gel TLC Rf is 0.63 and 0.67 in ethyl
acetate and hexane (1:1).
B. To a solution of 2.9 g of the reaction product of Part A in
25 ml of dry dichloromethane and 1.4 ml (1~02 g) of triethylamine at
0C is added with stirring 0.57 ml (0.848 g) of methanesulfonyl
chloride over 5 min. The resulting mixture is then stirred an
additional 20 min and shaken with 160 ml of diethyl ether and 80 ml of
cold (0C) dilute aqùeous hydrochloric acid. The organic layer is
then washed successively in brine, dilute aqueous potassium bicarbon-
ate, and brine, dried over sodium sulfate~ and concentrated under
reduced pressure to yield 3.5 9 of crude formula LIII compound:
(3RS)-3-hydroxy-7~-tetrahydropyran-2-yloxy-6~ ~(3'S)-3'-tetrahydro-
pyran-2-yloxy-trans-1'-octenyl~bicycl oL3. 3. O]octane, 3-methylsulfon-
ate.
C. Thiophenol (1.13 ml, 1.21 g) is added to a mixture of 1.12 gof potassium t-butoxide in 15 ml of dry dimethylsulfoxide (DMS0) under
a nitrogen atmosphere. To the solution of potassium thiophenoxide
thus prepared is added 3.5 9 of the reaction product of Part B in 8 ml
of dimethylsulfoxide. The resulting mixture is then stirred at
ambient temperature for 16 hr, whereupon additional potassium t-
butoxide is added so as to transform the solution to a distinct yellow
color. The resulting mixture is then stirred an additional 4 hr at
7~2
3704/3803/3823/3833/3879/3893
-55-
ambient temperature, dil uted with 100 m1 of diethyl ether and 100 mlof hexane, washed with 5% aqueous potassium hydroxide (200 ml) and
brine (200 ml), dried over magnesium sulfate, and concentrated under
reduced pressure to yield 5 g of a residue of crude formula LIV
5 compound: 3-phenyl thio-7-~-tetrahydropyran~2-yl oxy-6~-[(3'S)-3'-tetra-
hydropyran 2-yloxy-trans-1'-octenyl~bicycl o~3.3.0]octane. Chroma-
tography on 300 9 of silica gel, deactivated with 40 ml of diethyl
ether and 40 ml of trichloromethane and el uted wi~h 5% diethyl ether
in trichloromethane yields 301 9 of pure product. Silica gel TLC Rf
10 is 0.75 in 10% ethyl acetate in dichloromethane.
D. To a sol ution of 3.1 9 of the reaction product of Part C and
50 ml of dichloromethane at 0C is added with stirring over 10 min
2.43 9 of 85% m-chloroperbenzoic acid. The resulting mixture is then
stirred at 0C for 30 min, dil uted with 150 ml of dry ethyl ether,
15 washed w;th ice cold dilute aqueous potassium hydroxide and brine,
dried over magnesium sulfate, and concentrated under reduced pressure
to yield 3.4 9 of crude title product. Chromatography on 350 9 of
sil ica gel, deactivated with 70 ml of ethyl acetate and 21 ution with
500 ml o~ 30-50% ethyl acetate in hexane yields 2.90 g of pure title
20 product as a mixture of C-6 isomers. Silica gel TLC Rf's are 0.41,
0.45 and 0.48 in 30~ etnyl acetate in hexane (stereoisomers)~ N~R
absorptions are observed at 7.52-8.02, 5.30-5.67, 4.70, and 3.30-
4.13~.
Following the procedure of Exampl e 11, each o f ~he formul a LI
25 compounds is transformed to the corresponding formula LV 3-phenyl-
sul fonyl compound~
Example 12 (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2 (Formula LX:
X1 is -COOH, g is one, n is one, Rl6 and R17 are
hydrogen, R8 is hydroxy, Y1 is trans-CH=CH-, M1 is
~-OH:~-H, L1 is ~-H:b-H, and R7 is n-butyl), its methyl
ester and the corresponding (5Z) isomers thereof.
Refer to Chart C.
A. To a solution of 1.26 9 of the title product of Exampie 11
in 15 ml of dry tetrahydrofuran at -78C under a nitrogen atmosphere
35 is added dropwise with stirring 1.48 ml of 1.6 M n-butyllithium in
hexane over 1 min~ After 10 min 0.66 ~ of title product of Example 4
in 5 ml of dry tetrahydrofuran is added~ After 45 min 0.26 ml of
distilled acetic anhydride is added. Stirring is then continued at
71~ 3704/3803/3823/3833/3879/3893
-56-
-78C for 3 hr and a~ ambient tempera~ure for an additional 2 hr. The
resulting mixture is then shaken with 120 ml of diethyl ether and 80
ml of saturated aqueous ammonium chloride~ The orsanic layer is then
washed with 15 ml of brine, dried over magnesium sulfate, and concen-
trated uncier reduced pressure to yield 2.21 g of formula LVI productas a mixture of isomers: 3-[-acetoxy-o-(t-butyldimethylsilyloxy-
ethyl)-~-tolyl]-3-phenylsulfonyl-7a-(tetrahydropyran-2-yl)oxy-6~-
[(3IS)-3'-(tetrahydropyran-2-y1)oxy-trans-1'-octenyl~bicyclo[3O3.0l-
octane- R28, 9, R17, n, Rl8, Y1, M6, L1, and 227 are defined in
Examples 9 and 11. Silica gel TLC R~ ranye is 0.30-0.53 (8 spots)
(stereoisomers) in 25% ethyl acetate and hexane.
B. The mixture of isomeric products of Part A (2.21 9) and 40 ml
of methanol and 20 m1 of ethyl acetate is stirred at -20C with chips
of 5.6% sodium amalgam for 60 min. After decanting liquid, excess
amalgam and solids are rinsed by decantation employing 200 ml of
diethyl ether. The organic solutions are then combined, washed with
brine, dried, and concen~rated under reduced pressure to yield 1.8 g
of crude 2-decarboxy-2-(t-butyldimethylsilyloxymethyl)-2,5-inter-o-
phenylene-3,4-dinor-CBA2, 11,15-bis(tetrahydropyranyl ether). Chroma-
tography on 250 9 of sil ica gel, deactivated with 50 ml of diethyl
ether and eluted with 30% diethyl ether in hexane yields 1.06 9 o-f
pure product~ Silica gel TLC Rf's are 0~49, 0.56, and 0.62 (stereo-
isomers) in 30% diethyl ether and hexane. NMR absorptions are
observed at 7.20, 6.54, 5.22-5.80, 4072, 3.38-4.16 and 2.74-3.00~.
C. A solution of 1~06 9 of the reaction product of Part B in 1n
ml of dry tetrahydrofuran is treated with 3.2 ml of 0.75 N tetra-n-
butylammonium fluoride in tetrahydrofuran at ambient ternperature for
40 min. The resulting mixture is then diluted with 125 ml of diethyl
ether. The resulting solution is then washed with brine, dried over
magnesium sulfate, and concentrated under reduced pressure to yield a
residue of isomeric formula LVIII products: (5E)- and (52)-2-decar-
boxy-2 hydroxymethyl-2,5-inter-o-phenylene-3,4-dinor-CBA2, 11,15-bis-
(tetrahydropyranyl ether). Chromatography on 100 9 of silica gel,
deactivated with 20 ml of ethyl acetate and eluted with 25-50~ ethyl
acetate in hexane yields 0.40 9 of (5Z) isomer and 0.51 9 of (5E)
isomer. For the (5Z) isomer silica gel TLC R~'s are 0.31 and 0.35
(stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are
observed at 7.20, 6.51, 5.10-5.72, 4.69, 3.32-4.16~ and 2.76 3.00~.
- ' ~L~ 71Z 3704/3803/3823/3833/3879/38~3
For the (5E) isomer silica gel TLC Rf's are 0.20 and 0~24 (stereo
isomers) in 25Z ethyl acetate and hexane. NMR absorptions are
obserYed at 7.19, 6.50, 5~10-5.64, 4~70, 3.32-4.10, and 2.88-3.01~.
D. To a solution of 400 mg of the (5Z) reaction product of Part
C in 20 ml o~ dry acetone at -50C is added with stirring 1.0 ml of
Jones reagent (prepared as follows: 26.72 9 of chro~ium trioxide in
23 ml of concentrated sulfuric acid diluted with water to a volume of
100 ml). The resulting mixture is then allowed to warm to -20C over a
20 min period and stirred at -20C for 30 min. Excess Jones reagent
is then destroyed by addition of 0.5 ml of isopropanol. After 5 min
the reaction mixture is then shaken in 100 ml of e~hyl acetate and 80
ml of brine containing 0.5 ml of concentrated hydrochloric acid. The
organic layer is then washed twice in 50 ml of water containing a
trace (10 drops) o~ concentrated hydrochloric acid, twice in 50 ml of
water and in brine. The organic layer is then dried over magnesium
sulfate and concentrated under reduced pressure to yield 360 mg of
crude (5Z)-2,5-in~er-o-phenylene-3,4-dinor-CBA2, 11,15-bis(tetrahydro-
pyranyl ether), a formula LIX compound. Crude formula LIX compound is
then taken up in 30 ml of diethyl ether and extracted in the mixture
of 15 ml of water and 5 ml of methanol containing a trace amount (10
drops) of 45% aqueous potassium hydroxide. The extraction is repeated
6 times, until the acid is completely extrac~ed from the ethereal
solution. The aqueous extracts are then acidified to pH2 and ex-
tracted with ethyl ace~ate. The organic extract is ~hen washed with
brine, dried over magnesium sulfate, and concentrated under reduced
pressure to yield a residue of pure title product. Silica gel TLC ;s
a streak to about Rf 0.50 in ethyl acetate and hexane (1:1). Purified
acid is then converted to the corresponding ethyl ester by treatment
with excess ethereal diazomethane for 10 min. Following esterifica-
tion, the resulting reaction mixture is treated with ethyl acetate andwashed with dilute aqueous potassium hydroxide and brine. After dry-
ing and concentrating to a residue, chromatography on 20 9 of silica
gel deactivated with 4 ml of ethyl acetate and elution with 10X ethyl
acetate in trichloromethane yields 210 mg of (5Z)-2,5-inter-o-
phenylene-3,4-dinor-CBA2, methyl ester, 11915-bis(tetrahydropyranyl
ether~. Silica gel TLC Rf's are 0.52, 0~56, and 0.60 (stereoisomers)
in 25% ethyl acetate and hexane. ~MR absorptions are observed at
7.20, 6.45, 5~34-5.78, 4.70, 3.68, and 3.30-4.28~.
2~71;~ 3704/3803/3823/3833/3879/38~3
-58-
E. A mixture of 200 mg of methyl ester of Part D, 5 ml of aceticacid, 2.5 ml of water, and 1 ml of tetrahydrofuran is heated to 40C
and stirred for 4 hr. rhe resulting mix~ure is then diluted with 100
ml of ethyl acetate and washed with a mixture of 6 g of 85~ aqueous
5 potassium hydroxide in 20 ml of water and 30 9 of ice, washed with
brine (40 ml), dried over magnesium sulfate, and concentrated under
reduced pressure to yield 180 mg of crude (5Z)-2,5 inter-o~phenylene~-
3,4-dinor-CBA2, methyl ester. Chromatography on 20 g of silica gel
deactivated with 4 ml of ethyl acetate and elution with 100 ml o~ 50
10 ethyl acetate in ~richloromethane and 100 ml o~ SOqO ace~one in tri-
chloromethane yields 105 mg of pure product~ Silica gel TLC Rf is
0.57 in 40% acetone and trichloromethane and 0~52 in ethyl ace~ate.
NMR absorptions are observed at 7.20~ 6.43, 5~45-5.59, 3.65, 3.40-
4.20, and 3.18~. The mass spectrum of the bis TMS derivative exhibits
15 peaks of decreasing intensity a-t m/e 73, 75, 74, 147~ 43, 129, 41, 459
167, 59, and an M~-C5H11 peak at 485.2513.
f. To a solution of 105 mg of the reaction product of Part E in
5 ml of methanol and 2.5 ml of water under a nitrogen atmosphere is
added 0.33 9 of potassium carbonate. The resulting mixture is stirred
20 at ambient temperature for 20 hr whereupon a small quantity (5 drops)
of 45% aqueous potassium hydroxide is added. The resulting mixture is
stirred for an additional 4 hr at ambient temperatureO Thereupon the
mixture is shaken with 100 ml of ethyl acetate and excess cold dilute
aqueous hydrochloric acid. The organic layer is then washed with
25 brine, dried, and concentrated under reduced pressure to yield 100 mg
of pure (5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2. Silica gel TLC Rf
is 0.56 in the A-IX solvent system (the organic phase of an equil-
librated mixture of ethyl acetate, acetic acid, cyclohexane, and
water, 9:2:9:10). The mass spectrum of the tris TMS derivative
30 exhibits peaks of decreasing intensity at m/e 73, 75, 129, 167, 74,
55~ 69, 57, 147, and 45 and an M+-CH3 peak at 599~3418.
G. Following the procedure of Part D, 510 mg of the (5E3
reaction prodwct of Part C is transformed to 310 mg of (5E)-2,5-
inter^o-phenylene-3,4-dinor-CBA2, 11,15-bis(tetrahydropyranyl ether).
35 Silica gel TLC Rf is 0.41 in 25% ethyl acetate and hexane con-taining
1% acetic acid, and 220 mg of (5E)-295-inter-o-phenylene-3,4-dinor-
CBA2, 11,15-bis(tetrahydropyranyl ether~methyl ester. Silica gel TLC
Rf's are 0.48, 0.51, and 0.56 (stereoisomers) in 25% ethyl acetate and
6)~L7 ~ 370~/3803/3823/3~33/3879/3893
-59-
hexane. NMR absorptions are observed at 7.203 6.43, 5.26-5.64~ 4.70,
3.65, and 3.30 4.10~.
H, Following the procedure of Part E, ~he reaction product of
Part G (210 mg) is transformed to 110 mg of (5E)-2,5-inter-o-phenyl-
ene-3,4-dinor-CBA2, methyl ester. Silica ge1 TLC Rf is 0.57 in 40Z
acetone and trichloromethane and 0.46 in ethyl acetate. NMR absorp
tions are observed at 7.22, 6.44, 5.32-5047, 3.68, 3.50-4.08, and
3.106. The mass spectrum of the bis TMS derivative exhibits peaks of
decreasing intensity at m/e 73, 75, 129, 227, 167, 55, 57, 173, 74,
466 and an M+-CH3 peak at 541.3198.
I. Following the procedure of Part F, the reaction product of
Part H (110 mg) is transformed to 102 mg of (5E)-2,5-inter-o-
phenylene-3,4-dinor-CBA2. Silica gel TLC Rf is 0.50 in the A-IX
solvent system. The mass spectrum of the tris TMS deri~ative exhibits
peaks of decreasing intensity at m/e 73, 75, 167, 129, 524, 453, 285,
147, 434, 213, and an M -CH3 peak at 599.3424.
Example 13 (5E)-1,5-inter-m-phenylene-2,3,4-trinor-CRA2, its
methyl ester, and the corresponding (5Z) isomers.
Refer to Chart D.
A. Following the procedure of Example 12, Part A, a solution of
1.26 9 of the title product of Example 6 and 0.62 9 of the title
product of Example 5 are transformed to 2.3 9 of formula LVI compound.
Sllica gel TLC R~ range is 0.37-0.56 (7 spots)(stereoisomers) in 25%
ethyl acetate in hexane.
B. Following the procedure of Example 12, Part B, the reaction
product of Part A (2.3 9) is transformed to 1.0 9 of isomeric formula
LVII compounds: (5E)- and (5Z)~2-decarboxy-2-(t-butyldimethylsilyl-
oxvmethyl)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2, 11,15-bis(te-tra-
hyclropyranyl ether). Silica gel TLC Rf's are 0~47, 0.54 and 0.58
(stereoisomers) in 30% diethyl ether and hexane.
C. Following the procedure of Example 12, Part C, 1.0 9 of the
iswnerically mixed reaction product of Part B is transformed to 0.51 g
of (5Z)-2-decarboxy-2-hydroxymethyl-1,5-inter-m-phenylene-2,3~4-
trinor-CBA2, 11,15-bis(tetrahydropyranyl ether) and 0.40 g of (5E)-
2-deoarboxy-2-hydroxymethyl-1,5-inter-m-phenylene-2,3,4-trinor-CBA2,
11,15-bis(tetrahydropyranyl ether3. For ~he (5Z)-isomer, silica gel
TLC Rf's are 0.31 and 0.35 (stereoisomers) in 25~ ethyl acetate and
hexane. NMR a~sorptions are observed at 7.18~ 6.36, 5.19-5.65, 4~63,
-60-
4.58, 3,31-4.08, and 2.92.delta.. For the (5E)-isomer, silica gel TLC Rf's
are 0.23 and 0.27 (stereoisomers) in 25% ethyl acetate and hexane. NMR
absorptions are observed at 7.19, 6.37, 5.29-5.72, 4.67, 4.60, 3.30-
4.17, and 2.78.delta..
D. Following the procedure of Example 12, Part D, 510 mg of the
(5Z) reaction product of Part C is transformed to 310 mg of (5Z)-I,5-
inter-m-phenylene-2,3,4-trinor-CBA2, 11,15-bis(tetrahydropyranyl
ether) and 240 mg of (5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2,
methyl ester, 11,15-bis(tetrahydropyranyl ether). For the acid, sili-
ca gel TLC streak to about Rf 0.54 in 50% ethyl acetate and hexane.
For the methyl ester, silica gel TLC Rf's are 0.58, 0.63. and 0.68
(stereoismers) in 25% ethyl acetate and hexane. NMR absorptions are
observed at 7.28-8.00, 6.40, 5.13-5.73, 4.71, 3.89, and 3.28-4.08.delta..
E. Following the procedure of Example 12, Part E, 240 mg of the
methyl ester product of Part D is transformed to 140 mg of (5Z)-1,5-
inter-m-phenylene-2,3,4-trinor-CBA2, methyl ester. Silica gel TLC Rf
is 0.49 in ethyl acetate. NMR absorptions are observed at 7.28-7.93,
6.40, 5.34-5.48, 3.88, and 3.32.delta.. The mass spectrum of the bis TMS
derivative exhibits peaks of decreasing intensity at m/e 83, 85, 73,
47, 213, 75, 129, 48, 87, 77, and an M+-CH3 peak at 527.2996.
F. To a solution of 140 mg of the reaction product of Part E in
6 ml of methanol under a nitrogen atmosphere is added a solution of
0.20 g of 85% potassium hydroxide in 2 ml of water. The resulting
mixture is then stirred at ambient temperature for 7 hr, shaken with
200 ml of ethyl acetate and excess cold dilute aqueous hydrochloric
acid. The organic layer is then washed with brine, dried over magne-
sium sulfate, concentrated under reduced pressure to yield 110 g of
pure (5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2. Silica gel TLC Rf
is 0.60 in the A-IX solvent system. The mass spectrum of the tris TMS
derivative exhibits peaks of decreasing intensity at m/e 73, 271, 394,
129, 420, 510, 75, 147, 32, 74, and an M+-CH3 peak at 585.3234.
G. Following the procedure of Example 12, Part D, 400 mg of the
(5E) reaction product of Part C is transformed to 260 mg of (5E)-
1,5-inter-m-phenylene-2,3,4-trinor-CBA2, 11,15-bis(tetrahydropyranyl
ether) and 190 mg of (5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2,
methyl ester, 11,15-bis(tetrahydropyranyl ether). For the acid silica
gel TLC streak to about Rf 0.36 in 50% ethyl acetate and hexane. For
the methyl ester, silica gel TLC Rf's are 0.50, 0.53, and 0.57
L7~
3704/3803l3~23/3833/387g/38g3
(stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are
observed at 7.38-7.95, 6.q29 5.13-5.75, 40689 3.89, and 3.30-4.09~.
H. Following the procedure of Example 12, Part E, 190 mg o~ the
reaction product of Part G is transformed to 81 mg of (5E)-1,5-inter-
m-phenylene-2,3,4-trinor-C~A2, methyl ester. Silica gel TLC R~ is
0.51 in ethyl acetate. NMR absorptions are observed at 7.30-7.939
6~43, 5.45-5.59, 3.89, 3.50-4.14, and 3.09~. The mass spectrum of the
bis TMS derivative exhibits peaks of decreasing intensity at m/e 73,
213, 129, 75, 83, 452, 173, 85, 262, 362, and an M+-CH3 peak at
527.2996.
I. Following the procedure of Example 13, Part F, 81 mg of the
reaction product of Part H is transformed to 65 mg of (5E)-1,5-inter-
m-phenylene-2,3,4-trinor-CBA2. Silica gel TLC Rf is 0.60 in the A-IX
solvent system. The mass spectrurn of the tris TMS derivative exhibits
peaks of decreasing intensity at m/e 73, 271, 394, 75, 510, 129, 420,
147, 173, 395, and an M -CH3 peak at 585.3227.
Following the procedure of Examples 12-137 but employing each of
the various formula LV compounds described in and following Example 11
in each of the various formula XLIV described in and following Exam-
ples 9 and 10, there are prepared each of the various formula L com-
pounds in free acid or methyl ester form.
Example 14 9~-methyl-CBA29 methyl ester, 11,15-bis(tetrahydro-
pyranyl ether) (Formula LXXXIV: R16 is hydrogen, R37
is methyl, Z2 is -(CH2)3- and Rl8, Y1, ~6~ Ll, and R7
are as defined in Example 3) and the corresponding (SE)
and (5Z) free acids (Formula LXXXIII).
Refer to Chart G.
A. A suspension of 57% sodium hydride in mineral oil (1.90 9) is
washed with hexane and treated with 130 ml of dry dimethyl sulfoxide
(DMS0). The resulting suspension is heated at 65C for 1 hr under a
nitrogen atmosphere and the resulting solution cooled to 15C and
treated dropwise over 15 min with 10.0 9 of 4-carboxybutyltriphenyl-
phosphonium bromide. The resulting orange solution is stirred for 15
min at 10C and then treated dropwise over 15 min with a solution of
2.12 g of the title product of Example 3 in 20 ml of dry DMS0. The
resulting solution is then stirred at ambient temperature under a
nitrogen atmosphere for 60 hr, treated with 15 ml of water, stirred
for 30 min at ambient temperature, added to 200 ml of ice water and
~ 704/3803/3823/3833/3879/3~93
-62-
100 ml of brine, acidified with 1 N aqueous hydrochloric acid, andextracted with 900 ml of diethyl ether. The ethereal extracts are
then washed with 1 Q of water and 200 ml of brine9 dried over sodium
sul fate, and concentrated under reduced pressure to yield 4~8 g of a
5 yellow oil, thP formula LXXXIII carboxylic acid.
B. The formul a LXXXI II product and 42 ml of
diisopropylethylamine in 120 ml of acetonitrile a~ 10C under a
nitrogen atmosphere is treated with 15 ml of methyl iodide and allowed
to warm slowly to ambient temperature. The resulting suspension is
10 then stirred for 16 hr, treated with 3.0 ml of methyl iodide, stirred
for an additional 2 hr, added to 500 ml of brine, and extracted with 1
~ of ethyl acetate~ The organic extracts are then washed with 250 ml
of 0.5 N potassium bisulfate9 250 ml of saturated aqueous sodium
bicarbonate, 250 ml of brine, dried over anhydrous sodium sul fate, and
15 concentrated under reduced pressure to yield a solid residue. The
residue is then chromatographed on 500 9 silica gel, el uting with 870
acetone in hexane to yield 2.25 9 of title formula LXXXIV product.
NMR absorptions (CDCl3) are observed at 0.9, 1.05, 1.08, 3.66,
3.02-4.35, 4.70, and 4.95~. Infrared absorptions are observed at
20 1730, 1670, 1645, 1200, 1165, 1135~ 1080, 1035, 1020, 980, and 870
cm . Silica gel TLC Rf is 0.46 in ethyl acetate and hexane (1:3~ and
0.26 i n ethyl acetate and hexane (1:6~.
C. Alternatively the isomeric formula LXXXIII reaction produc~s
of Part A are separated into the (5E) and (5Z) title free acid pro-
25 ducts by chromatograhpy on acid washed silica gel el uting with 10-30%
ethyl acetate in hexane.
Following the procedure of Example 9, but employing each oF the
various formula LXXXI ketones in place of the Example 3 product, there
are prepared each of the various formul a LXXXIV methyl esters wherein
30 Z2 is -(CH2)3-
Further ~ollowing the procedure of Example 14, but employing a
formula LXXXII ~-carboxytriphenylphosphonium compound wherein Z2 is
other than -(CH2)3-, each of the various formula LXXXI ketones is
transformed to corresponding formula LXXXIV ester wherein Z2 is other
35 than -(CH2)3-
Example 15 ~5Z)-2-Decarboxy-2-hydroxymethyl-9~-methyl-CBA2,
11,15-bis(tetrahydropyranyl ether) (Formula LXXXVI:
R16, R37, Z2~ Rl8, M6, L1, and R7 are as defined in
L7~2
3704/3803/3823/3833/3879/3893
-63-
Example 14) and its (5E) isomer (formula LXXXVII).
Refer to Chart G.
A suspension of 0.16 9 of lithium aluminum hydride in 45 ml ofdry tetrahydrofuran at 0C under a nitrogen atmosphere is treated
dropwise with 1.98 9 of the title product of Example 14 in 15 ml of
dry tetrahydrofuran. The resultin~ suspension is stirred for 1 hr at
0C and thereafter for 1 hr at ambient temperature. The resulting
mixture is then cooled to 0C, quenched by addition of 0.16 ml of
water, 0.16 ml of 15X aqueous sodium hydroxide. After stirring for 1
hr at ambient temperature, treatment wi~h magnesium sulfate and
fil~ration with diatomaceous earth, rinsing with diethyl ether, yields
a mixture which is concentrated under reduced pressureO The resulting
product, 0.25 g, is chromatographed on 180 9 of silica gel, eluting
with 30% ethyl acetate in hexane to yield 1.03 9 of formula LXXXVII
product and 1.06 9 of formula LXXXVI product. For the formula LXXXVI
product NMR absorptions (CDCl3) are observed at 0.90, 1l09, 3.2-4.4,
4.72, 5.0-5.9~. Infrared absorptions are observed at 3470, 1760,
1200, 1135, 1120, 1075, 1035, 1020, and 980 cm . Silica gel TLC Rf
is 0.29 in ethyl acetate and hexane (35:65). For the formula LXXXVII
product NMR absorptions ~CDC13) are observed at 0.90~ 1.05~ 3.2-4.4,
4.6-4.95, 5.05-5.97~. Infrared absorptions are observed at 3470,
1670, 1200, 1125, 11109 1080, 1035, 1020, and 985 cm . Silica gel
TLC Rf is 0.36 in ethyl acetate and hexane (35:65).
Following the prooedure of Example 15, but employing each of the
various formula LXXXIV esters described following Example 14, there
are prepared each of the respective formula LXXXVI and formula LXXXVII
primary alcohols.
Example 16 (5Z)-9~-methyl-CBA2, methyl ester (Formula LXXXVIII: Xl
is -COOCH3, R8 is hydroxy, M1 is a-OH ~ H, and R16,
R17, Ll, R7, Y1, and Z2 are as defined in Example 15).
Refer to Chart G.
A. A solution of the formula LXXXVI title product of Example 15
in 38 ml of acetone at -20C under a nitrogen atmosphere is treated
over 5 min with 1.9 ml of Jones reagent (prepared by dissolving 133.6
9 of chromium trioxide in 115 ml concentrated sulfuric acid and
diluting with water to a volume of 500 ml3, stirred for 2 hr at -20C,
quenched by addition of 2.3 ml of isopropanol, s~irred for 40 min at
-20C, diluted with 200 ml of brine, extrac~ed with 400 ml of ethyl
7~
3704/3803/38~3/3833/3879/3893
-64-
acetate, washed with 600 ml of brine, dried over sodium sulfate, and
concentrated under reduced pressure to yield 1.01 g carboxylic acid
corresponding to the formula LXXXVI primary alcohol as a pale green
oil .
B. A solution of the product of Part A in 11 ml of acetonitri1e
at 15C under a nitrogen atmosphere is treated with 4.1 ml of diiso-
propyl ethylamine and 1.S ml of methyl iodide. The resul ting suspen-
sion is then stirred at ambient temperature for 17 hr, treated with
0.3 ml of methyl iodide, stirred for 2 hr a-t ambient temperature,
diluted with 50 ml of brine, extracted with 100 ml of ethyl acetate,
washed with S0 ml of 0.5 M potassium bisul fate, 50 ml of aqueous so-
dium bicarbonate and 50 ml of brine, dried over anhydrous sodium sul-
fate, and concentrated under reduced pressure to yield 1.02 g of the
methyl ester corresponding to the carboxylic acid product of Part A.
C. A solution of the product of Part B in 56 ml of a mixture of
tetrahydrofuran, water, and acetic acid (1:2:4) is hea~ed to 45C
under a nitrogen atmosphere for 3 hr, cooled, diluted with 2û0 ml of
brine, and extracted with 4ûO ml of diethyl acetate. The organic
extracts are then washed with 600 ml of sa~urated acqueous sodium
20 bicarbonate and 400 ml of brine, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure to yiel d 0.9 g of crude titl e
product as a yellow oil. Chromatographing on 100 g of silica gel,
eluting with hexane and ethyl acetate (3:7) yields 0.39 g of pure
title product as a colorless oil. NMR absorptions (CDCl3) are
25 observed at 0.89, 1~08, 3.5-4.35, 3 66, 5.0-5.7~. Infrared absorp-
tions are observed at 3360, 1740, 1670, 1455, 1435, 1370, 1240, 1225,
1195, 1170, 1075, 1020, and 970 cm . Silica gel TLC Rf is n.22 in
ethyl acetate and hexane (7:3).
Foll owing the procedure of Exampl e 16, but empl oyi ng each of the
30 various formula LXXXVI compounds described following Example 153 there
are prepared each of the various formula LXXXVIII 9~-methyl-C~A2
compounds wherein X1 is -COORl.
Example 17 (5E)-9~-methyl-CBA2, methyl ester (Formula LXXXIX:
R16, R17, Xl, Z2, R8, R1, M1, L1, and R~ are as
defined in Example 16).
Refer to Chart G.
A. Following the procedure of Example 15, Part A, 0.60 g of the
formula LXXXVII product of Example 15 is transformed to the carboxylic
L~ 712 370~/3803/3823/3833/3879/3893
-65-
acid corresponding to the formula LXXXVII primary alcohol, yielding
0.66 9 of a green oil.
B. Following the procedure of Example 16, Part B, the product of
Part A above (0.66 g) is transformed to the methyl ester corresponding
to the carboxylic acid produc~ of Part A, yielding 0.58 9 of a yellow
oil.
C. Following the procedure of Example 16, Part C, the product of
Part B above (0.58 9) is transformed to 0.25 9 of title product as a
colorless oil. NMR absorptions (CDCl 3) are observed at 0O90~ 1.05,
1 ~.30, 3.66, 3.75-4.25, 5.0-5O7~. Infrared absorptions are observed at
0 3360, 1740, 1670, 1455, 14357 1250, 1225, 1195, 1170, 1075, 1020, and
970 cm~ . Silica gel TLC R~ is 0.22 in ethyl acPtate and hexane
(3:7).
Following the procedure of Example 17, but employing each of the
various formula LXXXVII compounds described following Example 15,
there are prepared each of the various formula LXXXIX products wherein
Xl i S -COOCH3.
Example 18 (5Z)-9~-methyl-CBA2.
A solution of 0.28 9 of the title product of Example 16 in 8 ml
of methanol is stirred at ambient temperature under a nitrogen atmos-
phere ~nd treated with i ml of 8 M aqueous sodium hydroxide. The
resulting yellow solution is then stirred for 5 hr at ambient tempera-
ture under a nitrogen atmosphere, diluted with 90 ml of ice and brine,
acidified to pH2 with 1 N hydrochloric acidl extracted with 360 ml of
ethyl acetate, washed with 120 ml of brine, dried over anhydrous so-
dium sulfate, and concentrated under reduced pressure to yield 0.25 g
of crude title product. Chromatography on 30 9 of silica gel, eluting
with the A-IX solvent system (the organic phase of an equillibrated
mixture of ethyl acetate, acetic acid, cyclohexane, and water,
9:2:5:10), yields 0.235 9 of pure title product as a colorless oil.
NMR absorptions (CDCl3) are observed at 0.89, 1.08, 3.5-4.35, 5.0-5.7,
6.05~. Infrared absorptions are observed at 3340, 2660, 1710, 1240,
1205, 1175, 1130, 1075, 1055, 1020, and 970 cm~ . Silica gel TLC Rf
is 0.25 in the A-IX solvent system.
Following the procedure of Example 18 each of the various methyl
esters prepared following Example 16 is transformed to the corres-
ponding carboxylic acid.
~` ~L2~ 7~2 3704/3803/3823/3833/3879/3893
-66-
Example 19 (5E)-9R-methyl-CBA2.
Following the procedure of Example 18, 0.25 g of the title
product of Example 17 is transformed to 0.21 g of title product as a
colorless oil. NMR absorptions (CDC13) are observed at 0.90, 1.06,
3.5-4.3, 5.0-5.7, and 5.93~. Infrared absorptions are observed at
3340, 2660, 1710, 1300, 1240, 1175, 1130, 1075, 1055, 1020, and 970
cm . Silica gel TLC Rf is 0027 in the A-IX solvent system.
Each of the various carboxylic acids corresponding to LXXXVIII
and LXXXIX wherein X1 is -COOH- can be prepared from the corresponding
formula LXXXIII reac~ion products by acid hydrolysis of the tetra-
hydropyranyl ether protecting groups of C-ll and C-150 ~The (5Z)
LXXXIII reaction products from Example 14, Part C go to formula
LXXXVIII products; and the (5E) LXXXIII reaction products from Example
14, Part C go to formula LXXXIX products.]
15Following the procedure of Example 19, but employing each of the
various formula LXXXIX methyl esters described following Example 17,
there are prepared each of the various corresponding carboxylic acids.
Example 20 2~-(t-butyldimethylsilyloxymethyl)-5~-methyl-7-oxo-
3-tetrahydropyran-2-yl-oxy-bicyclo~3.3.0~octane
20(Formula LXII: n is the integer one, R3l is t-butyl-
dimethylsilyl, and R3i3 is tetrahydropyranyloxy).
Refer to Chart E.
A. A solution of 40.6 g of 3~-benzoyloxy-5~-hydroxy-2~-hydroxy-
methyl-1~-cyclopentaneacetic acid, ~-lactone in 250 ml of dimethyl-
formamide, stirring at 0C under a nitrogen atmosphere, is treated
with 25 9 of imidazole in 28 g of t-butyldimethylsilyl chloride. The
resulting solution is then stirred for 67 hr at ambient temperature,
added to 500 ml of water, extracted with three 500 ml portions of
diethyl ether, washed with 500 ml of lO~o aqueous potassium bisulfate,
500 ml o~ aqueous sodium bicarbonate and 500 ml of brine, dried over
sodium sulfate, and concentrated under reduced pressure to yield 59.9
g of 3-benzoyloxy-5a-hydroxy-2~-(t-butyldimethylsilyloxymethyl)-1~-
cyclopentaneacetic acid, ~ lactone as a white solid. NMR absorptions
(CDCl3) are observed at 0006, 0.91, 2.1-3.12, 3.74, 4.94-5.54, 7.24-
7.67, and 7.9-8.2~. Infrared absorptions are observed at 1780, 1720,
1600, 1585, 1490, 12709 1255, 1180, 1115, 1100, 1070, 1050, 830, 790,
and 710 cm . Silica gel TLC Rf is 0.20 in ethyl acetate and hexane
(1:4).
2~L~7~2
3704/3803/3823/3833/3879/3893
-67 -
Bq A solution of 59.1 9 o~ the reaction product of Part A and
500 ml of absolute methanol, stirring at ambient temperature under a
nitrogen atmosphere, is treated with 35 ml of a 25~0 solution of sodium
methoxide and methanol. The resulting reaction mixture is then
stirred for 90 min at ambiént temperature ~nd quenched by addition of
9.5 ml of glacial acetic acid. Methanol is removed under reduced
pressure and the resulting residue diluted with 500 ml of saturated
aqueous sodium bicarbonate. The resulting mixture is then extracted
with two 500 ml portions of ethyl acetate, washed with 300 ml of
saturated aqueous sodium bicarbonate in 200 ml of brine, dried over
sodium sulfate, and concentrated under reduced pressure to yield 58 9
of an oily solid, crude 3,5-dihydroxy 2~-(t~butyldimethylsilyloxy
methyl)-1~-cyclopentaneacetic acid, (~ lactone. This crude product is
then chromatographed in 800 9 of silica gel, eluting with 20-75~o ethyl
acetate in hexane to yield pure title product as a white crystal
solid~ Melting range is 60.5C to 62C. NMR absorptions (CDCl~) are
observed at 0~063 0.90, 1.7-3.0, 3.67, 3.9-4.4, and 4.7-5.13~. Silica
gel TLC Rf is 0.3 in 50% ethyl acetate in hexane.
C. A solution of 37.3 9 of reaction product of Part B in 400 ml
of methylene chloride, stirring at 0C under a nitrogen atmosphere, is
treated with 18 ml of dihydropyran and 0.14 9 of pyridine hydrochlor-
ide. The resulting solution is skirred at ambient temperature for 13
hr, treated with an additional 3 ml of dihydropyran and 30 mg of
pyridine hydrochloride, stirred for an additional 4 hr, washed with
two 400 ml portions of saturated aqueous sodium bicarbonate and 400 ml
of brine, dried over anhydrous sodium sulfate, and concentrated under
reduced presssure to yield 49 9 of a pale yellow oil, crude 5~-
hydroxy-3~-tetrahydropyran-2-yloxy-2~-(t-butyldimethylsilyloxymethyl)-
1~-cyclopentaneacetic acid, ~ lactone. Chromatography on 800 9 of
silica gel, eluting with 0-75% ethyl acetate in hexane yields 37 9 of
pure product as a colorless oil. NMR absorptions (CDCl3) are observed
at 0.05, 0.90, 1.62, 2,0-3.0, 3.6, 3.2-4.4, 4.67, and 4.8-5.2~.
Infrared absorptions are observed at 1780, 1255, 1175, 1160, 1116,
1080, 1035, 1020, 1005, 975, 335, and 775 cm . Silica gel TLC R~ is
0.25 in hexane and ethyl acetate (2:1).
D. A solution of 28 ml of dimethyl methylphosphonate in 800 ml
of dry tetrahydrofuran at -70C under a nitrogen atmosphere is treated
with 160 ml of 1.56 M n-butyllithium in hexane3 stirred for 30 min at
3704/3803/3823/3833/3879/3893
-68-
-70C. The resultiny mixture, maintained at -70C, is then treated
dropwise over 30 min with 41~7 9 of reaction product of Part C in 200
ml of tetrahydrofuran. The resulting solution is then stirred at
-70C for 1 hr, allowed to warm9 stirred for an additional 2.5 hr at
ambierit temperature, quenched by addition of 14 ml of glacial acetic
acid, added to 1 ~ of brine, extracted with three 700 ml portions of
diethyl ether, washed with 500 ml of brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to yield 63 9
of a yellow oil, crude 6~-(t-butyldimethylsilyloxymethyl)-3-dimethyl-
phosphonomethyl 3-hydroxy-2-oxa-7a-~etrahydropyranyloxy bicyclo[3r3.0~
octane~ Chromatography on 800 g of silica gel eluting with 50-75X
ethyl acetate in hexane yields 44.2 9 of pure title product as a
colorless oil. NMR absorptions (CDCl 3 ) are observed at 0.05,
0.89, 1.23-3.02, 2.2-4.37, 4.70, and 4.99~. Infrared absorptions are
observed at 3380, 1255, 2235, 1120, 1050, 1035, 835, and 775 cm 1.
Silica gel TLC Rf is 0.25 in ethyl acetate~
E. A suspension of 29.2 g of chromium trioxide in 700 ml of
methylene chloride, stirring at ambient temperature under a nitrogen
atmosphere, is treated rapidly with 50 ml of pyridine, treated with
dry diatomaceous earth, stirred for 5 min, and then trea~ed with 23.8
g of title product of Part ~ in 60 ml of methylene chloride. The
resulting suspension is then stirred for 45 min at ambient temperature
under a nitrogen atmosphere and filtered through 300 9 of silica gel,
eluting with 2 Q of ethyl acetate in acetone (2:1). Concentration
under reduced pressure yields 24 9 of a brown yellow oil, crude
3~-(t-butyldimethylsilyloxymethyl)-2~-(2'-dimethylphosphonomethyl-2'-
oxoethyl)-4a-tetrahydropyranyloxy-pentanone. High pressure liquid
chromatography of 12 9 of the crude product on silica gel eluting with
20% acetone in methylene chloride yields 4.54 g of pure product as a
colorless oil. NMR absorptions (CDCl 3) are observed at 0.05, 0.88,
2.8-4.5, 3.77, and 4.86~. Infrared absorptions are observed at 1745,
1715, 1255, 1130, 1115, lQ60, 1025, 835, 810, and 775 cm . Silica
gel TLC Rf is 0.27 in 20% acetone in methylene chloride and 0~3 in
ethyl acetate.
F~ A degassed suspension of 0.52 9 reaction product of Part E,
0.15 9 anhydrous potassium carbonate, and 0.59 9 18-crown-6 ether in
20 ml toluene are stirred at 75C for 6 hr under a nitrogen atmosphere
and thereafter cooled to 0C. The resulting solution is then washed
:~ZC~ 2
~ - 3704/3803/3823/3833~3879/3893
-69-
successively with 20 ml brine, a solution of 15 ml water and 5 ml
brine, and 20 ml brine, dried over anhydrous sodium sulfate, and
concentrated to yield a brown residue crude 6~-t-butyldimethylsilyl-
oxymethyl-7~-tetrahydropyran-2-yl-oxybicyclo~3.3.0]oct-1-en-2-one,
filtering through 7 9 of silica gel and eluting with hexane and ethyl
acetate (70 ml, 1:1) yields 0.31 9 of product as an oil. High
pressure liquid chromatography (10 ml fractions, 3.8 ml/minute flow
rate) on silica gel, eluting with hexane and ethyl acetate (3:1)
yields 0.20 g of pure product as a colorless oil. NMR absorption
(CDCl3~ o~ the trimethylsilyl derivative are observed at 0.06, 0.90,
1.20-3.20, 3.20-4~85, and 5.85-6.0~. Infrared absorptions are
observed at 17109 1630, 12509 1130, 1115, 1075, 1030, 965, 870, 835,
810, 775 cm . Silica gel TLC Rf is 0.34 in hexane and ethyl acetate
(2:1).
G. A suspension of 0.35 9 of anhydrous copper iodide in 12 ml
of anhydrous diethyl ether at -20C under an argon atmosphere is
treated dropwise with 2.0 ml of 1.4 M methyllithium. The resulting
solution is then stirred at -20C for 15 min, treated at -20C
dropwise over 1.5 hr with a solution of 0.22 9 of the reaction product
of Part F in 12 ml of anhydrous diethyl ether. The resulting
suspension is then stirred at -20C for 2 hr, added to 50 ml of 1 M
aqueous ammonium chloride, extracted with 150 ml of diethyl ether,
washed with 50 ml of brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to yield 0.23 9 of crude title
product as a pale ye1low oil. Chromatography on 30 g of silica gel,
eluting with ethyl acetate and hexane (1:4) yields 0.22 9 of pure
title product as a colorless oil. NMR absorptions (CDCl3) are
observed at C.05, 0.90, 1.16, 1.3-2.9, 3.3-4.4, and 4.63~. Infrared
absorptions are observed at 1745, 1255, 1135, 1110, 1095, 1075, 1n35,
30 1020, 835, and 775 cm . Silica gel TLC Rf is 0.32 in ethyl acetate
and hexane (1:4).
Example 21 N-methyl-(1-fluoro-5-tetrahydropyranyloxypentyl)-
phenylsulfoximine (Formula XCII: Z2 is -(CH2)32- and
Rlo is tetrahydropyranyl.
Refer to Chart H.
Diisopropylamine (0.59 9) is dissolved in 21 ml of tetrahydro-
furan and the resulting mixture cooled to -78C with stirring under an
argon atmosphere. Thereafter triphenylmethane is addedg for use as an
~ 3L~2~L 7~ 3704/3803/3823/3833/387g/3893
-70-
indicator~ and a solution oF n-butyllithium and hexane is added
dropwise until the resulting mixture attains a pink color. After
stirring for an additional 75 min, the resulting mixture is treated
with 1.50 g of N-methyl-(5-tetrahydropyranyloxypentyl)-phenylsulfox-
imine dissolved in 6 ml of dry tetrahydrofuran. The resulting mixtureis then stirred for an additional 30 min at 78C. Thereafter excess
perchloryl fluoride (FClO~) is bubbled through the solution for 4-5
min~ during which time a stream o~ argon is also bubbled through the
mixture for safety reasons. The resulting mixture is then stirred at
additiunal 90 min at -78C and then the reaction is quenched by
addition of 5% aqueous sodium bicarbonate. After equilibration of the
reaction mixture to ambient temperature, the mixture is diluted with
additional 5% aqueous sodium bicarbonate and extracted with methylene
chlorideO The organic extracts are then washed with brine, dried over
maynesium sulfate, and concen~rated under reduced pressure to yield
1.64 g of a yellow oil. Chromatography on silica gel columns in a
series, eluting with ethyl acetate and hexane (1:1) yields 0.18 9 of
the formula XCII title product as a mixture of diastereomers. Silica
gel TLC Rf in ethyl acetate and hexane (1:1) are 0.54 (less polar
isomer) and 0.45 (more polar isomer). NMR absorptions (CDCl3) for the
less polar isomer are 1;2-2~15~ 3~65~ 3~68~ 3~1-4~1~ 4~4-4~8~ 5~5~ and
7~4-8~1C~ NMR absorptions (CDCl3) for the more polar isomer are
1~15-2~20~ 3~63~ 3~1-4~1~ 4~45-4~65~ 5~27~ and 7~4-8~
Following the procedure of Example 21~ but employing each of the
various formula XCI phenylsulfoxamines, there are prepared each of the
various corresponding formula XCII fluorinated phenylsulfoxamines.
Example 22 5-Fluoro-2-decarboxy-2-hydroxymethyl-CBA2, 1~ 15-
tris(tetrahydropyranyl ether). (Formula XCIV: R16 and
R17 are both hydrogen, R1o is tetrahydropyranyl, Z2 iS
-(CH2)3-, n is the integer one, R18 is
tetrahydropyranyloxy, Y1 is trans-CH=CH-, M6 is
~-tetrahydropyranyloxy:~-hydrogen, R3 and R4 of the L
moiety are both hydrogen, and R7 is n-butyl)O
Refer to Chart H.
Diisopropylamine (164 mg) and triphenylmethane (1.5 mg) are
dissolved in 4 ml of dry tetrahydrofuran and the resulting solution i5
cooled to -78C under a nitrogen atmosphere~ A solution of n-butyl-
lithium and hexane is added until a faint pink color is attained.
~7~ ~ 3704/3803/3823/3833/3879/3893
-71-
This solution is then stirred an additional 80 min. Thereafter, 0.488g of the title product of Example 21 in 4 ml of dry ~etrahydrofuran is
added dropwise. Thereaf~er 608 mg of 7-oxo-3-tetrahydropyran-2-yl-
oxy-2~-[(3'S)-3'-tetrahydropyran 2-yloxy-trans-1'-octenyl] bicyclo-
C3.3.0]octane ~Formula XCIII: Rl6, Rl7, n, Rl8, Yl, M6, Ll~ and R7 areas defined for the title product) in 4 ml of tetrahydrofuran is added
to the reaction mixture. After 4 min, the resulting mixture is
quenched by addition of saturated aqueous ammonium chloride and ethyl
acetate is thereafter added to the reaction mixture, which is main-
tained at -78C. The resulting mixture is then allowed to warm until
solids separate. Thereupon additional ethyl acetate is added, the
reaction extracted with brine. The ethyl acetate layer is then dried
over sodium sulfate and concentrated under reduced pressure.
An a1uminum amalgam is then prepared by reacting 0.31 9 of 20
mesh aluminum with 2.5 ml of aqueous mercuric chloride followed by
wash;ng with ethyl acetate and diethyl ether. The residue from the
ethyl acetate layer (described in the preceeding paragraph) is dis-
solved in 5 ml of tetrahydrofuran and the solution cooled to 0C-
This cooled solution is then treated with aluminum amalgam, 2 ml of
water, and 1 ml of glacial acetic acid. The resulting mixture is then
stirred for 2 hr at 0C and 16 hr at 20C. The reaction is then
diluted with ethyl acetate and filtered with diatomaceous earth. The
ethyl acetate layer is then washed with 5YO aqueous sodium bicarbanate
and saturated brine, dried over sodium sulfate, and concentrated under
reduced pressure to yield 0.96 9 as an oily residue. Chromatographing
over 100 9 of silica gel and eluting with 500 ml of 15~ ethyl acetate
in mixed hexanes~ 500 ml of 25% ethyl acetate in mixed hexanes, 300 ml
o~ 50% ethyl acetate in mixed hexanes, and 800 ml of 50% acetone in
methylene chloride, taking 20 ml fractions, yields a less polar isomer
in fractions 22-26 (80 mg) and a more polar isomer in fractions 30-36
(74 mg). These isomers represent the C-5 diastereomers of the formula
XCIV product. For the less polar isomer, NMR absorptions (CDCl3) are
observed at 0.65-2.65, 3.15-4.15, 4.35-4.75, and 5.25-5.75~ For the
more polar isomer, NMR absorptions (CDCl3) are observed at 0.6 2.659
3.10-4.15, 4.40-4.7, and 5.2-5.7~. Silica gel TLC R~ for the less
polar isomer is 0.66 and for the more polar isomer is 0.57 in ethyl
acetate and mixed hexanes (3:7).
Following the procedure of Example 22, but employing each of the
2~ 3704/3~03/3823/3833/3879/3893
-72~
various formula XCIII ketones, there are obtained each of the various
formula XCIV intermediates wherein Z2 is -(CH2)3-.
Further following the procedure of Example 22, but substituting
each of the various fluorinated phenylsulfoximines described following
Example 21, there are prepared from the various formula XCIII ketones
each of the various formula XCIV products wherein Z2 is other than
-(CH2)3--
Example 23 5-Fluoro-2-Decarboxy-2-hydroxymethyl-CBA2 (more polar
isomer) (Formula XCV: R16, R17, Z2~ n, R8, M1, L1, and
R7 are as defined in Example 17).
Refer to Chart H.
The title product of Example 22 ~74 mg) is dissolved in 2 ml of a
mixture of tetrahydrofuran, water, and glacial acetic acid (2:2:1) and
the resulting mixture stirred under a nitrogen atmosphere. The reac-
tion mixture is maintained at ambient temperature for 17 hr, there-
after at 40C for 7 hr, and finally at 23C for an additional 24 hr.The resulting mixture is then diluted with ethyl acetate, washed with
5% aqueous sodium bicarbonate and sa~urated brine, dried over sodium
sulfate, and concentrated under reduced pressure ~o yield 52 mg of
crude title product. Chromatography over silica gel, eluting with
acetone and methylene chloride (60:40) yields 19 mg of pure title
product. NMR absorptions (CDC13) are observed at 0.6-2.60, 2.6n-3.30,
3.30-4.15, 5.1-5.9~. l3C-NMR absorptions (CDCl3) are observed at
135.8, 133,0, 117.5 (d J=18Hz), 77.4, 73.3, 62c6, 57.6, 46.4, 41.1,
38.0, 37.2, 36.2 (d J=5 Hz), 31.9, 31.8, 31.2, 29.5 (d J=29Hz3, 25.2,
22.5, 14.0~. Silica gel TLC Rf is 0.280 in acetone and methylene
chloride (1:1).
Example 24 S-Fluoro-2-decarboxy-2-hydroxymethyl-CBA2 (less polar
isomer)
Following the procedure of Example 23, 85 mg of less polar title
product of Example 22 are transformed to 25 mg of pure title product.
NMR absorptions (CDCl3) are observed at 0.5-2.5, 3.1-4075, and 5.05-
5.8~. C-NMR absorptions (CDCl3) are observed at 137.0, 132.6, 77.0,
73.6, 62.3, 57.4, 45O5~ 41.6, 36.9, 36.5, 34.4 (d J-3.1Hz)~ 32.5 (d
J=5.4Hz), 31.8, 31~7, 29.2 (d J=28.9Hz)9 25.4, 22.6, 2204, and l4.0~.
Silica gel TLC Rf is 0.33 in acetone and methylene chloride.
Following the procedure of Examples 23 and 24, but employing the
various diastereomeric products described following Example 22, there
'7~
3704/3803/3823/3833/3879/38g3
-73-
are prepared each of the various diastereomers curresponding toformula XCY.
Example 25 5-fluoro-C8A2 (more polar isomer) (Formula LXXVI: Z2~
n~ R8, Y1, Ml, Ll, and R7 are as defined in Example
23).
Refer to Chart H.
The platinum oxide catalyst is prepared by suspending 46 mg of
85% platinum oxide in 9 ml of water and hydrogenating the resulting
mixture at ambient temperature and pressure for 34 min. To this
suspension is added 58 mg of sodium bicarbona~e and 18 mg of the title
product of Example 23 dissolved in 2 ml of acetone. The resulting
mixture is then warmed to 60C and oxygen bubbled therethrough for 80
min. The reaction mixture is then filtered through diatomaceous earth
and the filter cake washed in water. The filtrate is then acidified
to pH4 with 5X aqueous sodium hydrogen sulfate and extracted with
ethyl acetate~ The organic extracts are then dried over magnesium
sulfate and concentrated under reduced pressure to yield 21 mg of pure
title product. NMR absorptions (CDCl3) are observed at 0.6-2.8,
3.0-4.2, and 4.65-5.8~ l3C-NMR absorptions (CDCl3) are observed at
20 176l99 135.5, 133.2~ 118.5 (d J=17.5Hz), 7707, 7~.5, 57.3, 46.5, 41.0,
38.2, 37.0, 36.2 (d J=4.8Hz), 32.3, 31.7, 31.1 (d J=13.5Hz), 28.5 (d
J=28.3Hz), 25.2, 22.6, 21.0, and 14.0~. Silica gel TLC Rf is 0.39 in
the A-IX solvent system.
Example 26 5-Fluoro-CBA2 (less polar isomer).
Following the procedure of Example 25, 24 m~ of the title product
of Example 24 yields 23 mg of pure title product. NMR absorptions
(CDCl3) are observed at 0.6-2.9, 3.3-4.2, 5.0-6.0~. C-NMR absorp-
tions (CDCl3) are observed at 176.8, 135.4, 132.9, 118.3 (d J-18~2Hz),
77.69 73.4, 57.2, 46.3, 41.2, 37.8, 3608, 34.6 (d J=2.7Hz), 32.8,
30 32'41 31.7, 28.7(d J=28.4Hz), 25.2, 22.6, 21.1, and 14.C~. TLC Rf is
0.50 in the A-IX solvent system.
The reaction products of Example 25-26 are obtained as diastereo-
meric mixtures of (5E) and (5Z) geometric isomers. These geometric
isomers are characterized herein as "less polar" and "more polar"
isomers based on TLC motilities~ The isomers of these 5-fluoro-CBA2
compounds correspond to the (5E) and (5Z) geometric isomers of C~A2
itself. On the basis of relative biological activities, the more
polar 5-fluoro-CBA2 isomer yields more potent pharmacological effects
Z~ 7~ 370~/3~303/3823/3833/3879/3893
-74-
and on this basis could be assigned the (5Z) structure based on phar-
macological considerations alone, However, the C-NMR data suggests
the more polar isomer corresponds to the (5E) structure of the
5-fluoro-C~A2 compound.
Following the procedure of Examples 25-26, there are prepared
each of the various formula XCVI 5 fluoro-CBA2 diastereomers from the
starting materials described following Example 24.
Further following the procedures known in the art, each of the
various 5-fluoro CBA2 compounds described in and following Examples
24~25 is transformed to the corresponding formula XCVII 5~fluoro-CBA~
analogs.
Example 27 (5Z) 9~ methyl-CBA2 adamantylamine salt
The title product of Example 18 (54 mg), (5Z)-9~-methyl-CBA2 in
6 ml of diethyl ether is combined with 23 mg of adamantylamine. After
10 min the precipitate forms which is thereafter stirred for 12 hr,
decanted, and concentrated under reduced pressure to yield 68 mg of a
solid, pure title product. Melting range is 110-114C.
Example 28 (5Z)-9~-methyl-CBA2, calcium salt hydrate.
The title product of Example 18 tOo95 9), 9~-methyl-(5Z)-CBA2,
calcium oxide (0.064 9), freshly boiled water (9.2 ml), and distilled
tetrahydrofuran (6 ml), are combined by heating to 50C under a nitro-
gen atmosphere with stirring for 20 min. The resulting mixture is
then filtered7 washed with tetrahydrofuran, and concentrated under
reduced pressure to yield a residue. The residue is then dissolved in
tetrahydrofuran -~10 ml) and concentrated 8 times to yield a cream-
colored fcam. This foam is then dissolved in 6 ml of tetrahydrofuran
which is dripped into anhydrous diethyl ether (95 ml). The resulting
suspension is then stirred for 15 min at ambient temperature under a
nitrogen atmosphere and filtered. The filter cake is then washed with
anhydrous diethyl ether and dried for 20 hr under reduced pressure at
ambient temperature to yield 0.686 9 of title product. Melting range
is 101-108C. Following atmospheric equillibration melting range is
80-117C. Infrared absorptions are observed at 33307 1670, 1555,
1455, 1345, 1310, 12709 1075, 1020, 970 cm~1.
Example 29 8a-hydroxy-7~-(3~-hydroxy-trans-l-octenyl)-tr
[4.3.1]nonan-4-one, 8,3'-bis(tetrahydropryanyl ether)
(Formula XXV: Rl87 Yl, M6, L1, R27, and n are as
defined in Example 19 R16 and R37 taken together
'7~
3704/3803/3823/3833/3879/3893
-75-
are-CH2- ) -
Refer to Chart A.
A~ The formula XXIV title product of Example 1 (4.0 g) and
benzophenone (2 9) in one l iter of methanol is photolyzed (3500 A
5 lamp) for 3 hr while argon is bubbled thr~ugh the solution. The
methanol is then removed by concentration under reduced pressure and
the residue chromatographed on 600 9 of silica gel eluting with a
mixture ranging from ethyl acetate in hexane (1:3) to 100~ ethyl
acetate. Compound XXVI,
10 1~-hydroxymethyl-7a-hydroxy-6~ (6~a-hydroxy-tran
1 '-octenyl )bicycloC3.3.0]octan-3-one, 7,3'-bis(tetrahydropyranyl
ether) is obtained as a white solid (3.45 9). Crystallization from
ethyl acetate in hexane yields a white solid with melting range
65-70C. NMR absorptions (CDC13) are observed at 0089, 1.17-2.90,
15 2.92-4.40, 4.69, and 5.24-5.77~o Infrared aborptions are observed at
3420, 1730, 1200, 1125, '1110, 1~)70, 1040, 1020, and 970 cm~l. Sil ica
gel TLC Rf i s 0.29 i n hexane and ethyl acetate (1: 4) .
B. A sol ution of 0.6 9 of the reaction product of Part A and
0.49 9 of p-toluenesulfonyl chloride in 30 ml of pyridine is cooled to
20 0C under argon for 70 hr~ added to 100 ml of ice, diluted with 300 ml
of water, and extracted with diethyl ether (800 ml ) . The ethereal
extracts are then washed with brine, dried over magnesium sulfate,
concentrated under reduced pressure, and chromatoyraphed eluting with
50% to 80% hexane i n ethyl acetate to yi el d 0.49 9 of formul a XXVI I
25 compound, 3-oxo- 7-te t rahydro pyran-2-yl oxy-6~- ~ (3 ' s ) -3 ' -tet ra hydro-
pyran-2-yloxy-trans-1'-octenyl]-1~-(p-toluenesolfonyl)-oxymethyl-
bi cycl o~3.3. O]octane, as a col orl ess oi l . NMR absorpt i ons ( CDCl 3 ) are
observed at 0.88, 1.06-2.9, 2.45, 3.17-4.35, 4052-4.83, 5.2 5.8, 7.37,
and 7.81 ~. Infrared absorptions are observed at 1740, 1600~ 1360,
30 1200, 1190, 1175, 1130, 1110, 1075, 1035, 1020, 970, and 820 cm~1.
Silica gel TLC Rf is 0.45 or 0.26 in ethyl acetate and hexane (1:1 or
1:2) .
C. A degassed solution of 0 49 9 of the reaction product of Part
B and 1 ml of t-butanol i n 50 ml of dry tetrahydrofuran at 0C under
35 an argon atmosphere is treated with 0.8 ~l of 1.7 M potassium
t-butoxide in tetrahydrofuran. After 5 min the reaction is allowed to
warm and the resulting brown solution stirred for 3 hr at ambient
temperature Thereafter 90 ml of brine is added and the mixture is
~L~ 7~ 3704/3803/3823/3833/3879/3893
-76-
extracted with 270 ml of ethyl acetate. The ethyl acetate extractsare then washed with 100 ml of saturated agueous sodium bicarbonate,
100 ml of brine, dried over anhydrous magnesium sulfate, concentrated
under reduced pressure, yielding 0.37 9 of a brown oil, and chroma-
tographed on 40 9 of silica gel eluting with hexane and ethyl acetate(2:1) to yield 0.32 9 of pure formula XXV title product as a colorless
oil .
D. Alternatively , a suspension of 207 mg of 57~ sodium hydride
in mineral oil and 1.08 9 of trimethyloxosulfonium iodide is treated
dropwise under a nitrogen atmosphere with 6 ml of dimethylsulfoxide.
The resulting grey slurry is then stirred at ambient temperature for
20 min, treated with 2.03 g of the title produot of Example 1 in 4 ml
of dry dimethylsulfoxide and stirred for 2 hr at ambient temperature.
Thereafter stirring is continued for 1 hr at 50C, ~he reaction
mixture is cooled and diluted with ZOO ml of water and thereafter
extracted with three 100 ml portions of diethyl ether. The combined
ethereal extracts are then washed with 200 ml of water, washed with
100 ml of brine, dried over anhydrous magnesium sulfate, concentrated
under reduced pressure, y1elding a brown oil, and chromatographed on
250 g of silica gel eluting with ethyl acetate and hexane (1:2) to
yield 453 mg of pure title product.
E. For title product prepared according to Part C or Part D
above, NMR absorptions (CDCl3) are observed at 0.25-2.75, 3.15-4.39,
4.68, and S.2-5.8~. Infrared absorp~ions are observed at 1725, 1665,
1135, 1080, 1040, 1020j 980 cm-1.
The mass spectrum exhibits a molecular ion at 446 and silica gel
TLC Rf is 0.30 in ethyl acetate and hexane.
Example 30 (5Z) and (5E)-6a~,9~-methano-CBA2 (Formula X: X1 is
-COOH~ ~l iS -(C~l2)3-, 21s is hydrogen, Rl6 and R17
taken together are methano, n is one, R8 is hydroxy, Y1
is trans-CH=CH-, M1 is ~OH:~-H, L1 is ~-H:~-H, R7 is
n butyl, and the C-5, C-6 positions are unsaturated).
Refer to Chart G~
A. A suspension of 452 mg of 57~ sodium hydride in mineral oil
and 30 ml of dimethylsulfoxide is heated to 65C for 1 hr under a
nitrogen atmosphere, cooled to 17C and thereafter treated over 15 min
with 2.39 9 of 4-carboxybuthyltriphenylphosphonium bromide. The
resulting red solution is then stirred for 15 min at 17-20C, treated
L71~ 3704/3803/3823/3833/3879/38g3
-77-
with a solution of 716 mg of the title product of Example 29, 6 ml ofdry dimethylsulfoxide, stirred for 43 hr at 40C, cooled to 0C,
treated with 3.5 ml of water, stirred for 30 min at 05, added to 75
ml of water and brine (2:1), acidified with one N aqueous hydrochloric
acid, and extracted with 225 ml of diethyl ether. The ethereal
extracts are then washed with 375 ml of water and 75 ml of brine,
dried over magnesium sulfate, concentrated under reduced pressure, and
chromatographed on 150 9 of acid-washed silica gel eluting with 10-25X
ethyl aceta~e in hexane to yield 290 mg of (5Z)-6a~,9~-methano-CBA2,
11,15-bis(tetrahydropyranyl ether), 70 mg of (5E)-6a~99~-methano-CBA2,
11,15-bis(tetrahydropyranyl ether), and 400 mg of a mix~ure of (5E)
and (5Z) formula LXXXIII isomers. Rechromatographing the isomeric
mixture on 150 9 of acid-washed silica gel yields an additional 50 mg
of (5E) isomer and 180 mg of (5Z) isomerO
For the (5Z) i somer NMR absorptions (CDCl 3) are observed at
0~5-2~85~ 3~22-4~4~ 4~70~ 4~9~5~75~ and 10~ Infrared absorptions
are observed at 3600-3000 (a broad band), 1740, 1710, 1240~ 12109
1135~ 1080~ 1035~ 1020~ 980~ and 870 cm 1. Silica gel TL0 Rf is 0~27
in hexane, ethyl acetate, and acetic acid (65 34 1)~ For the (5E)
isomer NMR absorptions are observed at 0~40-2~70~ 3~2-4~4~ 4~70~
5~0-508~ and 8~82~ Infrared absorptions are observed at 3600-30003
1740~ 1710~ 1460~ 1445~ 1200~ 1135~ 1075~ 1035~ 1020, and 980 cm 1,
Silica gel TLC Rf is 0~32 in hexane, ethyl acetate, and acetic acid
(65 34 1) ~
B~ A solution of 446 mg of the (5Z) reaction product of Part A
in 44 ml of acetic acid, water, and tetrahydrofuran (6 3 2) is heated
at 45C under a nitrogen atmosphere for 3 hr, cooled, added to 200 ml
of brine, extracted with 160 ml of ethyl acetate in hexane (3:2),
washed with 500 ml of brine, extracted with 120 ml of ethyl acetate
and hexane (3 2) dried over sodium sulfate, concentrated under reduced
pressure, yielding 0.38 9 of a yellow oil and chromatographed on 60 9
o~ acid washed silica gel eluting with 70% ethyl acetate in hexane to
yield 170 mg of pure (5Z) title product as a colorless oil. NMR
absorptions are observed at 0.5-2.90, 0089, 4.05, 4~85-5~89 and 6413~.
Infrared absorptions are observed at 3360, 2260, 1710, 1245, 1240,
1075~ 1025, and 970 cm 1O The mass spectrum for the tris-trimethyl-
silyl derivative exhibits a high resolution peak at 578~3653~ Silica
gel TLC R~ is 0.30 in the A-IX solvent system (~he organic phase of an
r~
Lo~u~O ~ 3704/3803/3823/3833/3~79/3~93
-7~-
equilibrated mixture of ethyl ace~ate, acetic acid, cyclohexane, andwater; 9:2:5:10).
C. Following the procedure of Part B above 90 mg of the (5E)
reaction product of Part A is converted to 46 mg of (5E) title product
as a colorless oil. NMR absorptions are observed at 4.40-2.8, 0~89,
4.06, and 5.0-5.85 ~. Infrared absorptions are observed at 3340,
2630, 1710, 1070, 970 cm~1. The mass spectrum exhibits a high
resolution peak at 578~3664. Silica gel TLC R~ is 0032 in the A-IX
solvent system.
Following the procedure of Examples 27-29l each of the various
formula X products is prepared wherein Rl6 and R17 are methano from
the corresponding formula LXXXI reactants of Chart G.
Accordingly9 the above examples provide methods for preparing
each of the various formula X CBA analogs of the present invention.
Example 31 9-deoxy-2',9a-methano-3-oxa-4,5,6~trinor-3,7^
~ 3l-inter-phenylene3-pGFla (Formula XI: X1 is COOH,
R20, R21, R23, and R~4 are all hydrogen, Z4 i S -CH2-,
R22 is ~-hydrogen, R~, Y1, M1, L1, and R7 are as
defined in Example 8) and its corresponding methyl
ester (X1 is -COOCH 3 ) .
Refer to Chart P.
A. A solution of methyl phenyl-N-methyl sulfoximine (3.39 g) in
dry tetrahydrofuran (60 ml), is alternately degassed and flushed with
nitrogen, cooled to -78C and treated dropwise over 7 min with 2.8 M
methyl magnesium Ghloride (7.16 ml). The resulting solution is
stirred at -78C for 30 min, then at 0C for 15 min. The reaction is
cooled to -78C and treated with a solution of 3-oxa-1,2,4,5,6-
pentanor-3,7-inter-m-phenylene-PGEl, 3-(t-butyldimethylsilyl ether),
11,15-bis~tetrahydropyranyl ether) (6.05 g), a formula CLXXI compound,
in dry tetrahydrofuran (35 ml). The resulting mixture is stirred for
1.75 hr while the temperature permitted to go from -78C to 0C and
then stirred for one hr at 0C. The reaction mixture is then diluted
with brine (170 ml) and extracted with diethyl ether. The ethereal
extracts are then washed successively with brine (170 ml), 0~5
aqueous potassium bisulfate (170 ml)~ saturated aqueous sodium bicar-
bonate (170 ml) and brine (170 ml), dried over magnesium sulfate,
filtered and concentrated to a yellow oil (800 9), 9-[(N methyl)-
phenylsulfoximinomethyl~-3-oxa-1,2,4,5,6-pentanor-3,7-lnter-m-
2 ~ ~L~ 370~/3803/3823/3833/3879/3893-79-
phenylene-PGFI, 3~(t-butyldimethylsilyl e~her), 11,15-bis(tetra-
hydropyranyl ether)O A degassed solution of 9-C(N-me~hyl)phenylsul-
foximinomethyl~-3-oxa-1,2,4,5,6-pentanor-3,7~inter-m-phenylene~PGF1,
3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether)
(8.0 g) in te~rahydrofuran (150 ml) is cooled to 0C, treated with 507~
acetic acid/water (45 ml) then immediately with aluminum amalgam under
nitrogen~ (The aluminum amalgam is prepared by washing 20 mesh alumi-
num, 8.00 9, with diethyl ether, 170 ml, methanol, 340 ml, mercuric
chloride, 8.03 93 in water, 275 ml, methanol, 170 ml, and diethyl
ether, 170 ml).
The resulting black suspension is stirred for 1075 hr during
which the reaction temperature is permitted to go from 0 to 15C
(slowly) then cooled to 0, treated with ethyl acetate (210 ml) and
stirred for an additional 30 min at 0C~ The suspension is filtered
through diatomaeous earth and the filter cake washed with ethyl
acetate. The combined filtrate is then washed with brine (300 ml),
0.5 M aqueous potassium bisulfate (300 ml), saturated aqueous sodium
bicarbonate (300 ml) and brine (300 ml), dried, filtered, and
concentrated to a yellow oil, crude formula CLXXI I compound (6.03 9),
9-deoxy-9-methylene-3-oxa-1,2,3,4,5,6-pentanor-3,7 inter-m-phenylene-P
GF1, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl
ether). The crude product is combined with that from a repeat
preparation to yield 10.1 9 of formula CLXXII product which is
chromatographed on silica gel eluting with 5YO ethyl acetate in
Skellysolve B (SSB, isomeric hexanes) to yield 6.93 g of 9-deoxy-
9-methylene-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFl,
3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether).
NMR absorptions are observed at 4.52-5.12 and 6.53-7.30~. Infrared
absorptions are observed at 1600 and 1655 cm 1. Silica gel TLC Rf is
0.39 in 10% ethyl acetate in hexane.
B. A degassed solution of 9-deoxy-9-methylene-3-oxa-1,2,4,5,6-
pentanor-3,7-inter~m-phenylene-P~F1, 3-(t-butyldimethylsilyl ether),
11,15-bis(tetrahydropyranyl ether), the reaction product of Part A,
(1.33 g) in dry tetrahydrofuran (70 ml) is cooled to 0C and treated
under nitrogen with 0.5 M 9-borabicycloc3.3~l~nonane (14 ml), dropwise
over 5 min. The colorless solution is stirred for 4.5 hr at 0 and
treated with 30% hydrogen peroxide (6 ml) followed by 3 N potassium
hydroxide (6 ml). The resulting suspension is stirred for an addi-
~ 2~3~L~12 3704/3803/3823/3~33/3~79/3893
-80-
tional 30 min at 0C and for 75 min while warming to room temperature.
The reaction mixture is transferred to a separatory funnel, diluted
with brine (300 ml) and ethyl aceta~e (300 ml). The layers are
separated, and the aqueous layer extracted with ethyl acetate (600
ml). The organic extracts are washed with brine (6 ml3, dried,
filtered, and contrated to formula CLXXIII product, a colorless oil
(3.3 g), 9~deoxy-9~-(hydroxymethyl)-3-oxa-1,2,4,5,6-pentanor-3,7
inter-m-phenylene-PGF1, 3-(t-bu~yldimethylsilyl ether)9 11,15 bis-
(tetrahydropyranyl ether). The crude formula CLXXIII product is
chromatographed on silica gel (300 9) in 35~ ethyl acetate in hexane
to yield 1.26 9 o~ 9-deoxy~9~-(hydroxymethyl)-3-oxa-1,2,4,5,6-
pentanor-3,7-inter-m-phenylene-PGF1, 3-(t-butyldimethylsilyl ether),
11,15-bis(tetrahydropyranyl ether) as a colorless oilc NMR absorp-
tions are observed at 4.73, 5.12-5.70, 6.52-7.23~. In~rared absor-
ptions are observed at 3480 and 1670 cm~1. Silica gel TLC R~ is 0.21in 35% ethyl acetate in hexane.
C. A degassed solution of 9-deoxy-9a-hydroxymethyl-3-oxa-
1,2,4,5,6-pentanor-397-inter-m-phenylene-PGF1, 3-(t-butyldimethylsilyl
ether), 11,15~bis(tetrahydropyranyl ether) (2.01 9), reaction product
of Part B, in dry methylene chloride (45 ml) is cooled to -5C under
nitrogen and treated with triethylamine (0.72 ml), then with methane-
sulfonyl chloride (0.76 ml). The resulting solution is stirred at
-5C for 5 min then for 75 min while warming to ambient temperature.
The reaction solution is poured over ice, and the resulting mixture
swirled for a few minutes then transferred to a separatory funnel and
partitioned between diethyl ether and brine. The layers are sepa-
rated, and the aqueous layer extracted with ether (400 ml)~ The
organic layer is washed with brine (200 ml) and saturated aqueous
~odium bicarbonate (400 ml), dried, filtered, and conctrated to a
formula CLXXIV product, a colorless oil (2.69 9), 9-deoxy-9~-mesyl-
oxymethyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1,
3~(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether).
This product (2.69 9) is chromatographed on silica gel (185 g) eluting
with 25% ethyl acetate in Skellysolve B to yield 1.99 g of 9-deoxy-9~/
-mesyloxymethyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1~,
11~15-bis(tetrahydropyranyl ether). NMR absorptions are observed at
2.95, 4.70, 5.20-5.70, and 6.52-7.22~. Silica gel TLC R~ is 0.30 in
35% ethyl acetate in hexane.
~r3~ 3
3704/3803/3823/3833/3879/3893
-8~ -
D. A degassed solution of 9-deoxy-9~ mesyloxymethyl-3-oxa-
1,2,4,5,6 pentanor-3,7-inter-m-phenylene-PGFl, 3-(t-butyldimethylsilyl
ether), 11315-bis(tetrahydropyranyl ether) (0.971 9) ~ ~he reaction
product of Part C, in dry tetrahydrofuran (35 ml) is cooled to 0C and
treated under nitrogen with 0.75 M tetrabutylammonium fluoride (2~6
ml). The resul~ing amber solutoin is stirred for 205 hr at 0-5C and
is partitioned between ethyl acetate (150 ml) and brine (150 ml). The
layers are separated, and the aqueous layer extracted with ethyl
acetate (300 ml). The organic layer is then washed with 0.5 M aqueous
ammonium chloride (150 ml), saturated aqueous sodium bicarbonate (300
ml) and brine (150 ml), dried, filtered and concentrated to give 0.82
g of formula CLXXV product, 9-deoxy 9~-mexyloxymethyl-3-oxa-1,2,4,5,6-
pentanor-3,7-inter-m-phenylene-PGF1, 11,15-bis(tetrahydropyranyl
ether. Infrared absorptions are observed at 3330 cm 1, Silica gel
15 TLC Rf is 0~37 in 50X ethyl acetate in hexane.
E. A degassed solution of 9-deoxy-9a-mesyloxymethyl-3-oxa
1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1, 11,15-bis(tetrahydro
pyranyl ether) (0.82 9), reaction product of Part D, is cooled to
-40C under argon and treated with 57qO sodium hydride (0.67 9~. The
resulting suspension is then stirred for 40 min at -40C then 15 min
at 0C. The suspension is stirred for an additional 20 min while
warming to room temperature and then stirred for 2.5 hr at reflux.
The reaction is then cooled to 10C, diluted with ice cold brine (2nO
ml) and extracted with ethyl acetate (450 ml). The ethyl acetate
extracts are then washed with brine (300 ml), dried, filtered and
concentrated to give 0.72 9 of the formula CLXXVI crude product. The
crude product is chromatographed in silica gel (175 g) in 2570 ethyl
~cetate in Skel1ysolve B to yield 0.49 g of 9-deoxy-2',9~-methano-3-
oxa~l~2~4~5~6-pentanor-3~7~ 3l-inter-phenylene)-pGrl~ 11,15-bis-
(te~rahydropyranyl ether). NMR absorptions are observed at 4.77,5.32-6.03, and 6.52-7.22~. Infrared absorptions are observed at 3340
and 1670 cm 1, Silica gel TLC Rf is 0.56 in 35% ethyl acetate in
hexane.
F. A degassed solution of 9-deoxy-2',9~-me~hano-3-oxa-
1,2,4,5,6-pentanor-3,7-(1',3'-inter-phenylene)-PGFl, 11,15-bis(tetra-
hydropyranyl ether) (0.47 9~, reaction product o~ Part E, in dry glyme
(15 ml) is cooled to 0C and treated under nitrogen withmethyl bromo-
acetate (0.26 ml) followed by 57% sodium hydride suspension (0.136 g)O
~" 3704/3803/3823/3833/3879/3~93
-82-
Following vigorous effervescence, a white precipi~ate is formed. The
resulting suspension is stirred for 2~5 hr at 0-5C, diluted with ice
cold brine (200 ml) and extracted with ethyl acetate (450 ml~. The
ethyl acetate extracts are washed with brine (300 ml), dried over
magnesium sulfate, filtered and concen~ra~ed to a pale yellow oil
(0.62 9), formula CLXXVII compound, 9-deoxy-2',9a-methano-3-oxa-4,5,6-
trinor-3,7-(1',3'-interphenylene)-PGF1, methyl ester, 11,15-bis(tetra-
hydropyranyl ether). Infrared absorptions are observed a~ 1765 and
1740 cm~1.
G. A solution of 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3~7-
(1',3'-inter-phenylene)-PGF1, methyl ester, 11,15-bis(tetrahydro-
pyranyl ether) (0.62 9), reaction product of Part F, in acetic acid
(15 ml), water (7.5 ml) and tetrahydrofuran (5 ml) is reacted at 45C
under nitrogen for 2.75 hr, cooled and diluted with ice cold brine
(200 ml). The resulting suspension is extracted with ethyl acetate
(400 ml), and the organic extracts washed with brine (400 ml),
saturated aqueous sodium bicarbonate (600 ml) and brine (200 ml). The
ethyl acetate extracts are then dried over magnesium sulfate, filtered
and concentrated to give 0.44 g of pale yellow oi1.
This crude product is chromatographed on silica gel (60 9) in 507O
ethyl acetate in Skellysolve B to yield 0.37 9 of product which was
crystallized to yield 0.216 9 of title product, 9-deoxy-2',9a-methano-
3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl, methyl ester.
Melting range is 82-84C. NMR absorptions are observed at ~.77, 4.62,
5.42-5.63, and 6.53-7.25~. Infrared absorptions are observed at 3520,
3400, and 1735 cm 1. Silica gel TLC R~ is 0.30 in 35X acetone in
methylene chloride.
H. A solution of 9-deoxy-2'-9a-methano-3-oxa-4,5,6-trinor-3,7~
(1',3'-inter-phenylene)-PGF1, methyl ester (0.15 9), reaction product
oF Part G, in 5% potassium hydroxide in 9:1 methanol-water (5.5 ml) is
stirred at 0C under nitrogen. The solution is turbid initially and a
precipitate forms within 5 min. The reaction is then stirred for one
hr at 0C, diluted with ice cold brine (90 ml), acidified with 1 N
hydrochloric acid, and extracted with ethyl acetate (180 ml). The
ethyl acetate extract is then washed with brine (270 ml), dried over
magnesium sulfate, and concentrated under reduced pressure to yield a
waxy, semi-solid (0.131 9), which is crystallized to yield 0.105 9 of
title product, 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-
7:1~
~~` 3704/3~03/3823/3833/3879/3893
-~33-
inter-phenylene)PGF1. Melting range is 131-133C. NMR absorptions
are observed at 4.68, 5.48-5.72~ 6.68-7.22. Infrared absorptions are
observed at 3460, 32809 1735, 1720, and 1700 cm~1.
I. The dosage at which the title compounds should be adminis-
tered to achieve their ef~ect, chiefly anti-platelet aggregation or
blood pressure lowering, will vary according to the potency of the
particular compound under study, When given orally, the compounds
will show a desired effect in man at a dose from about 0.05 to about
50 mg~kg orally, preferably from about 0.1 to about 5 mg/kg. The
compounds 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-
phenylene)-PGF1, methyl ester, given to a rat orally at a dose of 1
mg/kg lowered blood pressure 44 mmHg. After 52 min the blood pressure
was still lower 14 mm. Intravenous dosages for the desired effect are
from about 1 to about 500 ng/kg/min in man, preferably from about 10
to about 100 ng/kg/min.
Example 32 9-Deoxy-2l~9a-methano-3-oxa-4 9 5,6-trinor-3,7-(1',3'-
inter-phenylene)-16,16-difluoro-PGF1 (Formula XI: X1
is ~COOH, L1 is -fluoro:~-fluoro, R20, R20, R21, R23,
and R24 are a1l hydrogen, Z4 is -CH2-, R22 is
~-hydrogen, R8, Y19 M1, and R7 are as defined in
Example 8) and its corresponding methyl ester (X1 is
-COOCH3).
Refer to Chart P.
A. Diethyl ether (55 ml) tri-n-butylphosphine (2.28 9) and
cuprous iodide (2.13 g) are combined with stirring with the resulting
mixture being alternately degassed and flushed with nitrogen at 25C
for 1 hr. The resulting solution is then cooled to -78C and is
hereafter referred to as solution 32-I. Thereafter 60 ml of anhydrous
diethyl ether and 6.47 9 of m-bromo-phenol, t-butyldimethylsilyl ether
30 are combined and the resulting solution alternately degassed and
~lushed with nitrogen and cooled to -78C. After cooling, the
resulting mixture is treated with 44.16 ml of a 1.02 M solution of
t-butyllithium in n-pentane. This reaction mixture is then stirred at
-78C for 1 hr and hereinafter referred to as solution 32-II.
Solution 32-II is then transferred with stirring over 15 min to
solution 32-I under a nitrogen atmosphere. The resulting solution
changed in color from clear to yellow to an orange-brown to tan. The
resulting mixture is then stirred at 78C~ for 30 min and labelled
7~
3704/3803/3823/3833/3879/3893
84-
solution 32-IrI. Thereafter 4a~hydroxy-3~-(4'94'-difluoro-3'a-
hydroxy-trans~ octenyl)-2-methylene-cyclopentanone9 4,3'-bis(tetra-
hydropyran-2-yl ether)9 4 9, Example 25 of United Sta~es Patent
4,181,798, and 38 ml of anhydrous dry ethyl ether a~e combined with
stirring and the resulting mixture alterna~ely degassed and flushed
with nitrogen and thereafter cooled to -78C. The resulting solution
is referred to herein as solution 32-lV. Solution 32-IV is then added
to solution 32-III with vigorous stirring over 25 min at -78C under a
nitrogen atmosphere. The reaction mixture is then stirred a~ -78C
lQ for 30 min and thereafter transferred to 100 ml of 8~ glacia1 acetic
acid in diethyl ether (-405) with vigorous stirring under a nitrogen
atmosphere. The resulting mtxture is then diluted with brine and
extracted with diethyl ether. The ethereal extracts are then washed
with aqueous sodium bicarbonate în brine, dr1ed over sodium sulfate,
concentrated under reduced pressure~ and chromatographed on silica gel
eluting with 20Z ethyl acetate in Skellysolve ~ to yield 5.56 9 of
pure formula CLXXI compound: 16,16-difluoro-3-oxa-1,2,4,5,6-pentanor-
3,7-inter-m-phenylene PGE1, 3-(t-butyldime~hylsilyl ether), 11,15-
bis(tetrahydropyran-2-yl ether). NMR absorptions (CDCl 3) are observed
at 0.18, 3.1-5~0, 5.67, 6.52-6.88, and 6.88-7.2 ~. Infrared absorp-
tions are observed at 1745, 1600, 1585, 1490, 1275, 1260, 1200, 1155,
1125, 1075, 1035, 1025, 975, 840, and 780 cm 1, Silica gel TLC R~ is
0.36 and 0.41 in 25% ethyl aetate in Skellysolve B. Silica gel TLC
Rf is 0.5 in 5% acetone in methylene chloride.
B. Following the procedure of Example 31, Part ~, 3.~7 9 of the
reaction product of Part A of this example is converted to 2.98 9 of
formula CLXXII product as a colorless oil, 9-deoxy^9-methylene-3-oxa-
1,2,4,5,6-pentanor-3,7-inter-m-phenylene-16,16-difluoro-PGFl, 3-(t-
butylsilyl ether), 11,15-bis(tetrahydropyranyl ether). NMR absorp-
tions are observed at 0.17, 0.97, 1,0-3.2, 3.2-4.4, 4.4-5.0v 5.3-6.0,
and 6.4 7.3~. Infrared absorptions are observed at 1655, 1605, 1585,
1~85, 1275, 1260, 1200, 1144, 1125, 1080, 1025, 970, 870, and 780
cm~l. Silica gel TLC Rf is 0.31 and at 0.36 in 10% ethyl acetate în
hexane.
C. Following the procedure of Example 31, Part 83 2.83 9 of the
reaction product of Part B of this example is converted to 2.5 9 of
formula CLXXIII product as a colorless oil, 9-deoxy-9~-(hydroxy-
methyl)-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-16,16-difluoro-
3704/3803/3823/3833/3879/3893
-85 -
PGFl, 3~ butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl
ether). NMR absorptions (CDC13) are observed at 0.18, 0.98, 1015-3.09
3.0-4.5, 4.5-5.0, 5.3-5~9, and 6.4-7.3O~ Infrared absorptions are
observed at 3460, 1670, 1600, 1585, 1485, 1275, 1260, 1160, 1135,
5 1125, 1075, 1025, 975, 840, and 780 cm~ 1. Si 1 ica gel TLC R~ is 0. 28
in 35% ethyl acetate in hexane.
D. Following the procedure of Example 31, Part C, the reaction
product of Part C of this example (2.29 9) is converted to 1.83 9 of
formula CLXXIV product as a colorless oil, 9-deoxy-9a-mesyloxymethyl-
10 3-oxa-1,2,4,5,6-pentannr-3,7-inter-m-phenylene-16~16-difluoro-PGFl,
3-(t-butyldimethylsilyl ether~ 15-bis(tetrahydropyranyl ether~.
NMR absorptions are observed at 0.18, 0.989 1015-2.85, 2.95, 311-4.5,
4.5-5.0, 5.2-5.9, and 6.5-7.4~. Infrared absorptions are observed at
~930, 2860, 1605, 1590, 1490, 1465, 1440, 1360, 1275, 1200, 1175,
15 1120, 1025, 975, and 840 cm~1. Silica gel TLC Rf is 0.28 in 30~O ethyl
acetate and hexane.
E. Following the procedure of Example 31, Part D, 1.7 9 of the
reaction product of Part D of this example is converted to 1.6 9 of
formula CLXXV product as a yellow oil, 9-deoxy-9~-mesyloxymethyl-3-
20 oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-16,16-difluoro-PGFl,
11,15-bis(tetrahydropyranyl ether). Silica gel TLC Rf is 0.34 in
ethyl acetate and hexane (1:1 ) .
F. Following the procedure of Example 31, Part E, 1.52 9 of the
reaction product of Part D of this example is converted to 0.83 9 of
formula CLXXVI product as a ~hite foam, 9-deoxy-2',9a-methano-3-oxa-
1,2,4,5,6-pentanor-3,7-(1',3'-inter-phenylene)-16,16-difluoro-PGFl,
11,15-bis(tetrahydropyranyl ether). NMR absorptions are observed at
0.95, 1.05-2.95, 3.5-S.0, 5.3-6.09 and 6.5~7.23. Infrared absorptions
are observed at 3350, 2930, 1670, 1615, 15909 1465, 1280, 1200, 1120,
1070, and 975 cm~1. The mass spectrum exhibits peaks at 534, 451,
446, 402, and 348. Silica gel TLC Rf is 0.26 in ethyl acetate and
hexane (1:3) and 0.40 in acetone and methylene chloride (1:19).
G. Following the procedure of Example 31, Part F, 0~80 g of the
reaction product of Part F of this example is converted to 1.06 9 of
formula CLXXVII product as a colorless oil, 9-deoxy-2',9a-methano-3-
oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-16,16-difluoro-PGF1,
methyl ester, 11,15-bis(tetrahydropyranyl ether). Silica gel TLC Rf
is 0.44 in 5% acetone and methylene chloride.
` ~LZq~L~2 370~/3803/3823/3833/3879/3893
-86-
H. Followlng the procedure of Example 31, Part G, 1.0 9 of the
reaction product of Part G of this example is converted to 0.62 9 of
crystalline methyl ester title product, a Formula CLXXVIII white
solid. Recrystalli~ation from hexane in diethyl ether yields a
material with melting range 93-95C. NMR absorptions are observed at
O.9S, 1.10-2.90, 2.90-4.8, 5.4-5.8, and 6.4-7.3. Infrared absorptions
are observed at 3560, 3400, 1765, 1750, 1735, 1720, 1675, 1605, 1585,
1270, 1215, 1205, 1120, 1105, 1080, 1010, 970, and 770 cm 1. The mass
spectrum for the bis-trimethylsilyl derivative exhibi~s a high resolu-
tion peak at 582.2997. Silica gel TLC R~ is 0~35 in hexane and ethyl
acetate (1:43.
Following the procedure of Example 31, Part H, the reaction
product of Part H of this example (0.25 9) is converted to the
carboxylic acid title product (158 mg) as a crystalline solid.
Melting range is 128-~30C. NMR absorptions (COCD3) are observed at
0.9, 1.3-3.0, 3.0-4.6, 4.68, 4.8-5.5, 6.5-6.9, 5.5-5.9, and 6.6-7.3~.
Infrared absorptions are observed at 3570, 3480, 3370, 3220, 2800,
1740, 1720, 1605, 1585, 1235, 1210, 1125, 1105, 1080, 1000l and 970
cm 1. The mass spectrum for the tris-trimethylsilyl derivative exhi-
bits a high resolution peak at 640.3232. Silica gel TLC ~f is 0.18 in
the A-IX solvent sys~em.
Following the procedure of Examples 31 and 32, there are prepared
each of the various formula CLXXVIII products in free acid or ester
form from corresponding formula CLXXI reactants.
Formula CLXXVIII compounds wherein Y1 is unsaturated (trans- or
cis-CH=CH-) are trans~ormed to corresponding formula CLXXVIII com-
pounds wherein Y is saturated (-CH2CH2-) by hydrogenation, as
exemplified below:
Example 33 9-Deoxy-2',9a-methano 3-oxa-4,5,6-trinor-3,7-(1',3'-
inter-phenylene)-13,14-dihydro-PGFl (Formula XI: X1 is
C00~l, Y1 is -CH2CH2-, R20, R21, R23, and R24 are all
hydrogen~ Z4 iS -CH2-~ R22 iS ~-hydrogen, R8~ Ml~
and R7 are as defined in Example 8) and its corres-
ponding methyl ester (X1 is ~COOCH3~.
A. A solution of the methyl ester title product of Example 31
(0.341 9) in ethyl acetate (35 ml) is treated at ambient temperature
with 5% palladium-on-charcoal and hydrogenaked at atmospheric pres-
sure. The resulting suspension is then stirred for 70 minutes with a
~ ~2~L~7~ ~ 3704/3803/3823/3833/3879/3893
~87-
hydrogen uptake of 20 ml (atmospheric pressure). The resulting sus-
pension is then filtered through diatomaceous earth and the filter
cake washed with ethyl acetate. The combined filtrate is then con-
centrated under reduced pressure to yield a colorless oil which is
chromatographed on silica gel elu~ing wi~h ethyl acetate in Skelly-
solve B to yield 0.306 9 of title product (methyl ester3, a colorless
oil. NMR absorptions (CDCl3) are observed at 0.9, O. 1.07-1~23,
3.3-4.03, 3.77, 4.62, 6.52, and 7.27~. Infrared absorptions are
observed at 33S0, 2930, 2855, 1760, 1740, 1605, 1585, 1467, 1435,
1275, 1205, 1120, 1080, 1025, and 775 cm l. Silica gel TLC Rf is 0.54
in ethyl acetate.
~ . Following the procedure of Example 31, Part H, the title
product of Part A of this example (0.177 g) is converted to 0.23 g of
title product (free acid) as a solid. Recrystallization from ethyl
acetate in hexane yields 0.096 9 with melting range 121-123C. The
mass spectrum for the tris-trimethylsilyl derivatives exhibits a high
resolution peak at 606.3553 and other peaks at 591-535, 516, 427, 426,
275, 274, 173, and 157. Silica gel TLC Rf is n.27 in A-IX.
Example 34 9-Deoxy-2',9~ methano-3-oxa-495,6-trinor-397-(l',3'-
inter-phenylene)-PGF1 (Formula XI: X1 is COOH, R20,
R2l, R22, and R24 are all hydrogen, Z4 i S ~CH2~a R22 i S
a-hydrogen~ R8, Yl, M1, L1, and R7 are as defined in
Example 8) and its corresponding methyl ester (X1 is -COOCH3).
Refer to Charts Q and R.
A. A solution of 0.82 y of the reaction product of Example 31,
Part B, in 16 ml of methylene chloride is stirred at ambient tempera-
ture under nitrogen atmosphere and treated with diatomaceous earth
followed by 26 ml of Collins reagent prepared from 2.5 ml o-f yyridine
and 1.55 g of chromium trioxide in 50 ml of methylene chloride). The
r~sulting suspension is then stirred for 35 min at ambient temperature
under a nitrogen atmosphere and filtered through 3n 9 of silica gel~
eluting with 150 ml of ethyl acetate. Concentration under reduced
pressure yields 0090 g of a pale yellow oil. Chromatographing on 85 9
of silica gel eluting with 20% ethyl acetate in Skellysolve B yields
0.644 9 of pure formula CLXXXII aldehyde as a colorless oil, 9-deoxo-
9 formyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGEl9 3-(t-
..7~ ;2
, 3704/3803/3823/3833/3879/38g3
-88-
butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether). NMP~
absorptions are observed at 0.18, 0.88, 0.98, 1013-3.08, 3.23-4.35,
4.73, 5.25-5.75, 6.57-7,379 and 9.88~. Infrared absorptions are
observed at 2730, 1720, 1600, 1585, 1485, 1275, 1260, 1075, 1035,
1030, 1020, 975, and 840 cm~1. Silica gel TLC Rf is 0.47 in ethyl
acetate and hexane (1:3).
B. A degassed solution of 1.5 9 of the reaction product of Part
A and 0.36 ml of 1,8-diazobicyclo~5.4.0]undec-7-ene in 150 ml of
methylene chloride is stirred for 40 hr at ambient temperature under a
nitrogen atmosphere, washed with 100 ml of ice cold 0.15 M aqueous
potassium bisulfate, 100 ml of saturated aqueous sodium carbonateg and
100 ml of brine, dried over anhydrous sodium sul~ate and concen~rated
under reduced pressure -to yield 1.5 9 of formula CXCII product as a
yellow oil, 9-deoxy-9~-formyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-
phenylene-PGF1, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydro-
pyranyl ether). NMR absorptions (CDC13) are observed a~ 0.18, 0.89,
0.98, 1.1-3.2, 3.2-4.4, 4.68, 5.2-5.8, 6.58-7.4, and 9.22~. Infrared
absorptions are observed at 1725, 1600, 1585, 1485, 1440, 1275, 1260,
1200, 1160, 1130, 1075, 1035, 1020, 975, 870, and 840 cm~1. Silica
gel TLC Rf is 0.24 in ethyl acetate and hexane t1:3).
C. A solution of 1.5 9 of ~he reaction product of Part R in 4n
ml of methanol is treated with s~irring at 20C under a nitrogen
atmosphere over several minutes with 400 mg of sodium borohydride,
stirred for 20 min at 20C. The resulting mixture is then added to a
cold solution of 200 ml of brine and 32 ml of 0.1 M aqueous potassium
sulfate, extracted with 600 ml of ethyl acetate, washed with 200 ml of
saturated aqueous sodium bicarbonate in 200 ml of brine, dried over
anhydrous magnesium sulfate, concentrated under reduced pressure,
and chromatographed on 200 g of silica gel eluting with 35% ethyl
acetate in hexane to yield 1.37 g of formula CLCIII product as a
colorless oil, 9-deoxy-9~-hydroxymethyl-3-oxa-1,2,4,5,6-pentanor-3,7-
inter-m-phenylene-PGF1, 3-(t-butyldimethylsilyl ether), 11,15-(tetra-
hydropyranyl ether). NMR absorptions (CDCl 3) are observed at 0.17,
0.88, 0.99, 1.1-3.0, 3.0-4.35, 4.7, 5.25-5.85, and 6.5-7.4~. Infrared
absorptions are observed at 3460, 1665, 1605 9 1685, 1490, 1275, 1260 9
1200, 1160, 11359 1115, 1075, 1~120, 1005, 975, 840, and 780 cm~1.
Silica gel TLC Rf is 0.20 in 35% ethyl acetate in hexane.
D. A degassed solution of 1.32 9 of the reaction product of Part
_ 370~/3~03/3823/3~33/3879/3893
-89-
B in 0.47 ml of triethyl amine and 30 ml of methylene chloride at 20C
unde~ a nitrogen atmosphere is treated with 0.5 ml of methanesulfonyl
chloride, stirred for 5 min at 0C, warmed to 20C over 90 min, added
to 50 9 of ice, diluted with 150 ml of brine~ extracted with 450 ml of
diethyl ether, washed with 150 ml of brine and 300 ml of saturated
aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate,
concentrated under reduced pressure to yield an oil, and filtered
through 70 g of silica gel eluting with 30~ ethyl acetate in hexane to
yield 1.47 9 of mesylate corresponding to the starting material, i.e.,
the 9~ an~log of formula CLXXIV. Silica gel TLC Rf is 0.23 in 30qo
ethyl acetate in hexane.
E. A degassed solution of 1.47 9 of the reaction product of Part
D and 50 ml of dry tetrahydrofuran at 0C under a nitrogen atmosphere
is treated with 3.9 ml of 0.45 M tetra-n-butylammonium fluoride. The
resulting solution is ~hen stirred at 0C for 4 hr, treated with
another 0.5 ml of tetra-n-butylammonium fluoride, stirred for 30 min
at 0C, diluted with 150 ml of brine, extracted with 450 ml of ethyl
acetate, washed successively with 150 ml of 0.5 M aqueous ammonium
chloride, 300 ml of saturated aqueous sodium bicarbonate, and 150 ml
of brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure to yield 1.3 g of a yellow oil, the phenol corres-
ponding to the starting material, i.e., the 9~ isomer of ~he formula
CLXXV compound. Silica gel TLC Rf is 0.11 in 35~O ethyl acetate in
hexane.
F. A degassed solution of 1.3 g of the reaction product of Part
E in 75 ml of dry glyme at ~40C under a nitrogen atmosphere is
treated with 90 mg of 57% sodium hydride dispersion in mineral oil,
s~irred at -40 to -30C for 40 min, stirred at 0C for 15 min, stirred
at ambient temperature for 15 min, heated and refluxed for 5 hr,
cooled to ambient temperature5 added to 200 ml of ice cold glyme,
extracted with 450 ml of ethyl acetate, washed with 300 ml of brine,
dried over anhydrous on 175 9 of silica gel eluting with 25~o ethyl
acetate in hexane to yield 0.61 9 of the 9~ isomer corresponding to
the formula CLXXVI compound as a viscous oil. NMR absorptions are
observed at 0.90, 1.07-3.1, 3.1-4.4, 4~75~ 5~33-6~169 and 6~5-7~2
Infrared absorptions are observed at 3340, 1665~ 1610~ 1585~ 1500~
1465, 1135, 1110~ 1075, 1020, and 980 cm 1. Silica gel TLC Rf is 0.26
in 25% ethyl acetate in hexane and 0.23 in 5% acetone in me~hylene
~ L~ 3704/3803/3823/3833/3879/3893
-90 -
chloride,
Go A solution of 0.50 9 of the reaction product of Part F in 28
ml of methyl bromoace~ate in 16 ml of dry glyme at 0C under an argon
~tmosphere is treated with 0.14 9 of a 577O mineral oil dispersion of
sodium hydride. The resultirlg suspension is then stirred for 2.5 hr
at 0C, quenched with 200 ml of cold brine, extracted with 460 ml of
ethyl acetate, washed with 300 ml of brlne, dried over anhydrous
sodium su1fate, and concentrated under reduced pressure to yield 0.68
g of an oil, the 9~ isomer corresponding to the ~ormula CLXXVII
compound.
H. A solution of the reaction product of Part G (0.68 g) in 5 ml
of tetrahydrofuran, 7.5 ml of water9 and 15 ml of acetic acid is
heated for 2~5 hr at 45C, cooled, diluted with 200 ml of brine,
extracted with 400 ml of ethyl acetate, washed with 400 ml of brine,
washed with 200 ml of saturated aqueous sodium bicarbonate, and 200 ml
of brine, dried over anhydrous sodium sulfate, concentrated under
reduced pressure to yield an oil, chromatographed on 75 9 of silica
gel eluting with 307O hexane in ethyl acetate to 100% ethyl acetate to
yield 0.32 9 of title methyl ester as a white foam. Crystallization
from hot diethyl ether in hexane yields 0.23 g of pure ester product
as a white solid. Melting range is 85-87C. NMR absorptions (CDCl3)
are observed at 0.90, 1~07-2.9, 2.9-4.5, 4.61, 5.4-5.8. and 6.38-
7.34~. Infrared absorptions are observed at 3520, 34209 1735~ 1720,
1605, 1580, 1300, 1240, 1210, 1110, 1085, 1050, 1010, 970, 760, 720,
and 710 cm l. The mass spectrum of the bis-trimethylsilyl derivative
exhibits a high resolution peak at 546.3182. Silica gel TLC Rf is
0.14 in 30% ethyl acetate in hexane.
I. Following the procedure of Example 31, Part H, the title
product of Part H (1S8 mg) is transformed to the title free acid (129
mg) as a white solid. Melting range is 150-154C. NMR absorptions
are observed at 0.90, 1.07-3.5, 3.85-4.35, 4.70, 5~09-5.9, and
6.5-7.3~. Infrared absorptions are observed at 3380, 2640, 2560,
1730, 1605, 1580, 1260, 1230, 1115, 1050, 1025, 970, and 770 cm 1.
Following the procedure of Example 34, each of the various
formula XI compounds are prepared wherein R22 is ~-hydrogen. Further
following the procedure of Example 33, the various 9B-methano isomers
of Example 34 and corresponding formula XI compounds wherein Y1 is
cis- or trans-CH=CH- are hydrogenated to corresponding 13,14-dihydro-
12
3704/3803l3823/3833l387g/3893
-91
PGF l compounds.
Example 35 9-Deoxo-2',9-metheno-3-oxa-4~5,6-trinor-3,7~(1'93'-
inter-phenylene)-PGE1 (Formula XI: X1 is COOH9 ~20
R239 and R24 are all hydrogen~ Z~ is -CH2-, ~21
and R22 taken together form a valence bond, R8, Y1, M19
L19 and R7 are as defined in Example 8) and its
corresponding methyl ester (X1 is -COOCH3).
Refer to Chart T.
A. A degassed solution of the reaction product of Example 34,
Part A, (1.68 9) in dry tetrahydro~uran (50 ml) is cooled to 0C and
treated under a nitrogen atmosphere with 0.75 M tetrabutylammonium
fluoride ~4.37 ml). The resulting solution is then stirred at 0C for
2 hr, diluted with brine (300 ml), extracted with ethyl acetate,
washed with brine, dried over magnesium sulfate, filtered, and concen-
15 trated under reduced pressure to yield 2r3 9 of an oil~ The oil is
chromatographed on silica gel (160 9) in 25% ethyl acetdte in Skelly-
solve B yielding 1.21 9 of formula CCXI compound, 9-deoxo-9~-
formyl-1,2,405,6-pentanor-3,7-inter-m-phenylene-PGE1, 11915-bis(tetra-
hydropyranyl ether). NMR absorptions (CDCl 3) are observed at 0.88,
1~13-3~15~ 3~27-4~47~ 4~71~ 6~10~ 6.53-7.41, 9~27~ Infrared absorp-
tions are observed at 3345~ 2930~ 2860~ 2720~ 1735, 1715~ 1605, 1595
1585~ 1485~ 1450, 13709 1350, 1255~ 1235~ and 970 çm~1. Silica gel
TLC Rf is 0.12 i n 25% ethyl acetate and hexane and n . 39 i n 50~o ethyl
acetate in hexane.
8. A degassed solution of 0.28 9 of the reaction product of Part
A in 33 ml of glyme is cooled to -40C under argon and treated with
2.95 N methylmagnesium chloride in tetrahydrofuran (0.2 ml). The
reaction mixture is stirred at -40C for 15 min, stirred at 0C for 15
min, permitted to warm to ambient temperature, stirred at reflux for
115 hr under an argon atmosphere, cooledg diluted with ice cold brine
(150 ml), extracted with ethyl acetate (300 ml), washed with brine
(~00 ml), dried over magnesium sulfate, filtered, concentrated under
reduced pressure to yield 0.31 9 of an oil, and chromatographed on
silica gel eluting with 25% ethyl acetate in Skellysolve B to yield
0.16 9 of the formula CCXII compound, 9-deoxo-2',9-~etheno-3-oxa-
1,2,4,5,6-pentanor-3,7-(1',3'-inter-phenylene)-PGE13 11,15-bis(tetra
hydropyranyl ether). The mass spectrum of the trimethylsilyl deriva-
tive exhibits a molecular peak at 568 and other peaks at 466, 382,
3L 7 ~ 3704/3803/3823/3~33/387g/3893
-92~
364, 314, 297, 267, 255, 243, 230, 270, 153, and 85. Silica gel TLC
Rf is 0.25 in 25% ethyl acetate in hexane and 0.58 in 50~ ethyl
acetate in hexane.
C. A degassed solution o~ the reaction product of Part C (0.16
g) in dry glyme (5 ml) is cooled at -5C and treated with methylbromo
acetate (0.04 ml) under a nitrogen atmosphere. The resulting solution
is then treated with 50% sodium hydride dispersion in mineral oil (00
16 9). Precipitate forms in 5 min in the resulting suspension is
stirred for 1.5 hr at 0C, diluted with brine (100 ml), extracted with
ethyl acetate (240 ml), washed with brine (100 ml), dried over magne-
sium sulfate, filtered, concentrated to yield a brown residue ~hich
solidifies on refrigeration, and chromatographed on 25 9 of silica gel
eluting with 2C% ethyl acetate in Skellysolve e to yield 00136 9 of
the bis(tetrahydropyranyl ether) of a formula CCXIII compound: 9-
deoxy-2',9-metheno-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenylene)-PGE1,
methyl ester, 11,15-bis(~etrahydropyranyl ether)0 Melting range is
81-83C. The mass spectrum exhibits peaks at 366~ 384~ 3649 279~
247~230~ 215, 149~ and 85~ Silica gel TLC Rf is 0~45 in 5% acetone in
methylene chloride.
D. A solution of the reaction product of Part C (0.12 9) in
tetrahydrofuran (1 ml), water (2 ml) and acetic acid (4 ml) is heated
at 45C under a nitrogen atmosphere for 2~25 hr, cooled, and parti-
tioned between brine (100 ml) in ethyl acetate (90 ml)~ The layers
are separated and the aqueous layer extracted with ethyl acetate (160
25 ml). The organic layers are then washed successively with brine (1nO
ml), water (100 ml), saturated aqueous sodium bicarbonate (3~0 ml) and
brine (200 ml), dried over magnesium sultate3 filtered, concentrated
to yield 0~97 9 of a solid, and chromatographed on 30 9 of silica gel,
eluting with 85% ethyl acetate in hexane to yield 0.083 g of white
crystalline formula CCXIII title product in methyl ester form.
Recrystallization from diethyl ether in hexane yields 0~056 9 of pure
methyl ester title product. Melting range is 96-98C~ NMR
absorptions (CDCl3) are observed at 0.94, 3~86~ 3~92-4~28~ 4~72
5~58-5~86~ and 6a62~7~18~ Infrared absorptions are observed at 3420
35 1765~ 1665~ 1600~ 15750 1465~ 1440~ 1275~ 1215~ 1190~ 1105~ 1085~ 970~
and 770 cm 1. The mass spectrum for the trimethylsilyl derivative
exhibits a molecular ion at 554 and other peaks at 454~ 383~ 3659 3649
230~ 229, 225. Silica gel TLC Rf is 0041 in ethyl acetateO
3704/3803/3823/3833/38i9/3893
-93-
E. Following the procedure of Example 31, Part H3 the reactionproduct of Part D (0.19 g~ is converted to 76 mg of crystalline title
product in free acid form. Melting range is 150-152C. NMR
absorptions (CDC13) are observed at 0.91, 1.2-3.48, 3.88-4.15, 4.70,
5.62-4.66~ and 6.63 7.11. The mass spectrum for the trimethylsilyl
derivative exhibits a high resolution peak at 602.3251 and other peaks
at 512, 422, 287, 225, 174, and 173. Si1ica gel TLC R~ is 0.23 in the
A-IX solvent system.
Example 36 9 Deoxy-2',9-methano-3-oxa-4,5,6,13,14,15,16,17,18,-
19,20-undecanor-3,7 (1i,3'-inter-phenylene)-12-formyl-
PGF1, methyl ester (formula CCXXII: Xl is -COOCH3, Z4
is -CH2-, R20, R21, and R23 are hydrogen, R22 is
3-hydrogen, and R18 is tetrahydropyran-2-yl-oxy).
Refer to Chart U.
Ozone is bubbled through a solution of 0.72 9 of the reac~ion
product of Example 31, Part F, in 50 ml of absolute methanol at -78C
for 5 min. Thereafter oxygen is bubbled through the resulting solu-
tion for 5 min and the solution is treated with 16 ml of dimethyl
sulfide. After standing at 16 hr for 0C under a nitrogen atmosphere
and 2-1/2 hr at ambient temperature, the solution is diluted with 200
ml of ethyl acetate, washed successively with 100 ml o~ brine, 100 ml
of saturated aqueous sodium bicarbonate and 100 ml of brine, dried
over anhydrous sodium sulfate, concentrated under reduced pressure,
and chromatographed on 175 g of silica gel eluting with 357~ ethyl
acetate in hexane to yield 367 mg of title product as a colorless oil.
NMR absorptions (CDC13) are observed at 1.0-3.0, 3.1-4.5, 3.63,
G.45-7.34, and 9.77~0 The mass spectrum exhibits peaks at 388 and
304. Silica gel TLC Rf is 0.19 and 0.22 in 25~o and 30% ethyl acetate
in hexane.
Example 37 9-Deoxy-2l~9a-methano-2o-methyl-3-oxa-4~5~6
trinor-3,7-(1',3'~inter-phenylene)-PGF1 (Formula XI:
Xl~ Z4~ Rs~ R209 R21, R22, R23, R24, Y1, M1, and L1 are
as defined in Example 31 and R7 is n-pentyl) its methyl
ester (Z1 is -COOCH3), its 15-epimer (M1 is a-H:~ OH),
and 15-epimer methyl ester (M1 is -H:~-OH and Z1 is
-COOCH3).
Refer to Chart U.
A. A suspension of 56 mg of a 57~ sodium hydride dispersion in
L'7:~
3704/3803/3823/3833/3879/3893
-94-
mineral oil and 4 ml of tetrahydrofuran at 0C under a nitrogen atmos-
phere is treated with a solu~ion of 286 mg of dimethyl~2-octylphos-
phonate in 4 ml of tetrahydrofuran, stirred for 5 min at 0C, stirred
for l hr at ambient temperature, cooled to 0C, treated with a solu-
tion of 0.39 9 of title product of Example 36 and 4 ml of tetrahydro-
furan, stirred for 2-1/2 hr at ambient temperature, cooled in 0C,
added to a solution of 40 ml of ethyl acetate containing several drops
of acetic acid), extracted with 120 ml of ethyl acetate, washed with
30 ml of saturated aqueous sodium bicarbonate, washed with 30 ml o-f
brine, dried over anhydrous sodium sulfatel concentrated under reduced
pressure to yield an oil, and chromatographed on 60 9 of silica gel
eluting with 2570 ethyl acetate in hexane to yield 0.42 9 of a color-
less oil, 9,15-dideoxy-15-keto-2',9a-methano-20-me-thyl-4,5,6-trinor-
3,7-(1',3'-inter-phenylene)-PGFl, methyl ester, 11-tetrahydropyranyl
ether. NMR absorptions are observed at 0.89, 1.05-3.0, 3~5 4.37,
4.62, and 5.97-7.30~. The mass spectrum exhibits peaks at 414, 396,
323, 311, and 301. Silica gel TLC Rf is 0.26 in 25~ ethyl acetate in
hexane.
B. A degassed solution of 42 mg of sodium borohydride and 4 ml
20 of absolute methanol at -30C under a nitrogen atmosphere is ~reated
dropwise with a solution of 391 mg of the title reaction product of
Part A in 0.3 ml of methylene chloride and 3 ml of methanol, stirred
for 1-1/2 hr at -30C, quenched by careful addition of 0.2 ml of
glacial acetic acid, diluted with 70 ml of brine, extrac~ed with 210
ml of ethyl acetate, washed with 70 ml of saturated aqueous sodium
bicarbonate, washed with 70 ml of brine, dried over anhydrous sodium
sulfate, concentrated under reduced pressure to yield 0.42 9 of a
colorless oil, and chromatographed on 60 9 of silica gel eluting with
40% ethyl acetate in hexane to yield 0~36 9 of an epimeric mixture of
C-15 alcohols. Silica gel TLC Rf is 0.20 in 40Z ethyl acetate in
hexane.
C. A solution of the reaction products of Part B above in 3 ml
of tetrahydrofuran, 4O5 ml of water, and 9 ml of acetic acid is heated
to 45C under a nitrogen atmosphere for 2.5 hrs, cooled, diluted
washed with 100 ml of brine, extracted with 200 ml of ethyl acetate,
washed with lO0 ml of brine, washed with 300 ml of satureated aqueous
sodium bicarbonate and 100 ml of brine, dried over anhydrous sodium
sulfate, concentrated under reduced pressure to a yellow oil, and
7 ~ 370~/3803/3823/3833/3879/3893
-95-
chromatographed on 60 g of silita gel eluting with 20~o ethyl acetatein methylene chloride to yield 96 mg of 9 deoxy-2',9-methano-
20-methyl-3-oxa-4,5,6-trinor-3,7-(153-inter-phenylene)-15 epi-PGF1,
methyl ester as a colorless oil and 159 mg of 9-deoxy~2',9~-methano-
20-methyl-3-oxa-4,5,6 trinor-3,7-(1,3-inter-phenylene)-PGF1~ methyl
ester as a white solid. Recrystallization of the 15a-hydroxy compound
from hot hexane in diethyl ether yields 140 mg as a whi~e solid.
Melting range ls 79-82C. For the title product methyl ester, ~MR
absorptions are observed at 0.92, 1.08-3.0, 3.38-4.5, 4.64, 5.33-5.70,
and 6.5-7.4. The mass spectrum of the trimethylsilyl derivative
exhibits a high resolution peak at 56003375. Silica gel TLC Rf is
0.19 in 20% ethyl acetate in methylene chloride and 0 31 in 2nq~ hexane
in ethyl acetate. For the 15-epi compound, NMR absorptions (CDCl3)
are observed at 0.89~ 1.07-3.0, 3.7-4.33, 4.63, 5.5-5.8, and
6.55-7.37~. Infrared absorptions are observed at 3360, 1765, 1750,
1735, 1605, 1585, 14709 1440, 1205, 1120, 1080, 97Q, and 770 cm~1.
The mass spectrum for the trimethylsilyl derivative exhibits a high
resolution peak at 560.33S5. Silica gel TLC R~ is 0.35 in 20~o acetone
and methylene chloride and 0~45 in 20% hexane and ethyl acetate.
D. Following ~he procedure of Example 31, Part H, the 15~-
hydroxy title product of Part C ~94 mg) is transformed to 9-deoxy-
2l~9a-methano-2o-methyl-3-oxa-4~5~6-trinor-3~7~ 3-inter-phenylene3-
PGF1, title free acid, as a white solid, 81 mg~ Melting range is
144-146C, NMR absorptions (CD3COCD3) are observed at 0~8, 1.05-2.9,
302-4.5, 4~65, 5.38-5~56, and 6.6-7.2~. The mass spec~rum of the
trimethylsilyl derivative exhibits a high reso1ution peak at 618.3576.
Silica gel TLC Rf is 0.14 in the A-IX solvent system.
E. Further following the procedure of Example 31, Part H, the
15-epi title product of Part C (93 mg) is converted to 9-deoxy-2',9~-
methano-20-methyl-3-oxa-4,5,6-trinor-3,7-(1~3-inter-phenylene)-15-epi-
PGFl, a white solid, 72 mg. Melting range is 105-108C. MMR
absorptions (CD3COCD3) are observed at 0.90, 1.05-2.9, 3.2-4.3, 4.71,
5.0~5.84, and 6.5-7.34~. Sil;ca gel TLC Rf is 0.19 in the A-IX
solvent system.
Following the procedures of Examples 36 and 37, there are
substituted C-12 side chains according to the procedure of Chart U for
each of the various formula XI compoundsO
Thus, according to procedures described above, there are prepared
~2~
3704/3803/3823/3833/3879/3893
-96-
(5E)-9~-methyl CBA2 compounds,
(5Z)-9~-methyl-CBA~ compounds,
(5E)-5-fluoro-9~-methyl-CBA2 compounds,
(5Z)-5-fluoro-9~-methyl-CBA2 compounds,
(5E)-5-fluoro-CBA2 compounds,
(5Z)-5-fl uoro-CBA2 compounds,
(5E)-9g-methyl-2,5-inter-o-phenylene-3,4-dinor-C~A2 compounds,
(5Z)-9~-methyl-2,5-inter-o-phenylene-3,4~dinor-CBA2 compounds,
(5E) 9~-methyl-1,5-inter-o-phenylene-2,3,4-trinor-CBA2 compounds,
(5E)-9~-methyl-1,5-inter-o-phenylene-3,4,5-trinor-CBA2 compounds,
(5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds,
(5Z~-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds,
(5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds,
(5Z)-1,5-inter-m-phenylene-2,3,4~trinor-CBA2 compounds,
2,2-difluoro-(5E)-9~-methyl-CBA2 compoundsg
2,2-difluoro-(5Z)-9~-methyl-CBA2 compounds,
2,2,5-trifluoro-(5E)-9~-methyl-C8A2 compounds,
2,2,5-trifluoro-(5Z)-9~-methyl-CBA2 compounds,
2,2,5-trifluoro-(5E)-CBA2 compounds,
2,2,5-trifluoro-(5Z)-C3A2 compounds,
2,2-difluoro-(5E)-9~-methyl-2,5-inter-o-phenylene-3,4-dinor-CBA2
compounds,
2,2-difluoro-(5Z)-9~-methyl-2,5-inter-o-phenylene-3,4-dinor-CBA2
compounds,
2,2-difluoro-(5E)-9~-methyl-1,5-inter-o-phenylene-2,3,4-trinor-
CBA2 compounds,
2,2-difluoro-(5E)-9~-methyl-1,5-inter-o-phenylene-3,4,5-trinor-
CBA2 compounds,
2,2-difluoro-(5E)-2,5-inter-o-phenylene-3,4-dinor-CRA2 compounds,
2,2-difluoro-(5Z)-2,5-inter~o phenylene-3,4-dinor-CRA2 compounds,
2,2-difluoro-(5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2
compounds,
2,2-difluoro-(5Z)-1,5-inter-m-phenylene-2,3,4-trinor-C~A2
compounds,
trans-2,3^didehydro-(5E)-9~-methyl-CBA2 compounds,
~rans-2,3-didehydro-(5Z)-9~-methyl-CBA2 compounds,
trans-2,3-didehydro-(5E)-5-fluoro-9~-methyl-CBA2 compounds,
trans-2,3-didehydro-(5Z)-5-fluoro-9~-methyl-CBA2 compounds 9
- 370~/3803/3823/3833/3879/389
-97 -
trans-253-didehydro-(5E)-5-~luoro-CBA2 compounds,
trans-2 9 3-didehydro-(5Z)-5-fluoro-CBA2 compounds,
trans-2,3-didehydro- (5E)-9~-methyl-2l5-inter-o-phenylene-3,4-
dinor-CBA2 compounds,
trans-2,3-didehydro-(5Z)-9~-methyl -295-inter-o-phenyl ene-3,4-
dinor-CBA2 compounds,
trans-2,3-didehydro-(5E)-9~methyl-1,5-inter-o-phenylene-2,3,4-
trinor-CBA2 compounds,
trans-2,3-didehydro-(5E)-9~-methyl-1,5-inter-o-phenylene-3,4,5-
10 trinor-CBA2 compounds,
trans-2,3-didehydro-(5E)-2,5-inter-o~phenylene-3,4-dinor-CBA2
compounds,
trans-2,3-didehydro (5Z)-2,5-inter-o-phenylene-3,4-dinor-C~A2
compounds,
trans-2,3-didehydro-(5E)-1,5-inter-m-phenylene-2,3,4-tri nor-CBA2
compounds,
trans-2,3-didehydro-(5Z)-1,5-inter-m-phenyl ene-2,3,4-trinor-CRA2
compounds,
9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7- (1 ',3 '-i nter-
20 phenylene)-PGFl compounds,
9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7- (1 ' ,3 '-inter-
phenylene)-PGFl compounds,
9-deoxo-2',9-metheno-3-oxa-3,4,5-trinor-3,7-(1 ' ,3'-inter-
phenylene)-7,8-didehydro-PGEl compounds,
9-deoxo-2',9-metheno-3-oxa-3,4,5-trinor-3,7-(1 ' ,3'-inter-
phenylene)-PGEl compounds,
6a-oxo-9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-
phenylene)-PGFl compounds,
6a-oxo-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-
30 phenylene-PGFl compounds,
6aa-hydroxy-9-deoxy-2l~9a-methano-3-oxa-4~5~6-trinor-3~7-(l ',3'-
inter~phenylene)-PGFl compounds,
6aa-hydroxy-9-deoxy-2',9~-methano-3-oxa 4,5,6-trinor-3,7-(1 ',3'-
inter-phenylene)PGFl compounds,
6a~-hydroxy-9-deoxy-2~9a-methano-3-oxa-4~5~6~trinor-3~7-(l ',3'-
inter-phenylene-PGFl, and
6a~-hydroxy-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7- (1 ',3'-
inter-phenylene)-PGFl compounds1
iL7~Z
~~ 3704/3~03/3823/3833/3879/3893
-98-
in free acid or methyl ester form which exhibit the following side
chain substituents:
15-cyclohexyl-16,17,18,19,20-pentanor-;
17-(2~furyl3-18,19,20-trinor-;
16-(3-thienyl)oxy-17,18,19,20-~etranor-;
17-(3-thienyl)-18,19,20-trinor ;
15-methyl-;
16-methyl-j
15,16-dimethyl-;
-10 16,16-dimethyl-;
17~20-dimethyl;
16-fluoro-,
15-methyl-16-fluoro-;
16,16-difluoro-;
15-methyl-16,16-difluoro-;
17-phenyl-18,19,20-trinor-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-;
17-(m-chlorophenyl)-18,19,20-trinor-;
17-(p-fluorophenyl)-18,19,20-trinor-;
15-methyl-17-phenyl-18,19,20-trinor-;
16-methyl-17-phenyl-18,19,20-trinor-;
16,16-dimethyl-17-phenyl-18,19,20-trinor-;
16-fluoro-17-phenyl-18,19,20-trinor-;
16,16-difluoro-17-phenyl-18,19,20-trinor-;
16-phenyl-17,18,19,20-tetranor-;
15-methyl-16-phenyl-17,18,19,20-tetranor-;
16-(m-trifluoromethylphenyl)-17,18,19,20-tetranor-;
16-(m-chlorophenyl)-17,18,19,20-tetranor-;
16-(p-fluorophenyl)-17,18,19,20-tetranor-;
16-phenyl-18,19,20-trinor-;
15-methyl-16-phenyl-18,19,20-trinor-;
16-methyl 16-phenyl-18,19,20-trinor-;
15,16-dimethyl-16-phenyl-18,19,20-trinor-,
16-pher,oxy-17,18,19,20-tetranor-,
15-methyl-16-phenoxy-17,18,19,20 tetranor-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-;
16-(p-fluorophenoxy)-17,18,19~20-tetranor-;
3L2q~7~
3704/3803/3823/3833/3879/3893
~99
16-phenoxy-18319,20-trinor-,
15-methyl-16-phenoxy-18,19,20-trinor-;
16-methyl-16-phenoxy-18,19,20-trinor-;
15,16-dimethyl-16-phenoxy-18,19920-trinor-;
13,14-didehydro-;
15-cyclohexyl-16,17,18,19,20-pentanor-13,14-didehydro ;
17-(~-furyl)-18,19320-trinor-13,14-didehydro-;
16-(3-thienyl)oxy-17,18~19,20-tetranor-13,14-didehydro~,
17-(3-thienyl)-18,19 9 20-trinor-13,14-didehydro-;
15-methyl 13,14-didehydro-;
16-methyl-13,14-didehydro-,
15,16-dimethyl-13,14-didehydro-;
16,16-dimethyl-13,14-didehydro-;
17,20-dime~hyl-13,14-didehydro-9
16-fluoro-13,14-didehydro-;
15-methyl-16-fluoro-13,14 didehydro-;
16,16-difluoro-13,14-didehydro-;
15-methyl-16,16-difluoro-13,14-didehydro-;
17-phenyl-18,19,20-trinor-13,14-didehydro-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-didehydro-;
17-(m-chlorophenyl)-18,19,20-trinor-13,14-didehydro-;
17-(p-fluorophenyl)-18,19,20-krinor-13,14-didehydro-;
15-methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16-methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16,16-dime~hyl-17-phenyl-18,19,20-trinor-13~14-didehydro-;
16-fluoro 17-phenyl-18,19,20-trinor-13,14-didehydro-;
16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16-phenyl-17,18,19,20-tetranor-13,14-didehydro-;
15-methyl-16-phenyl-17,18,19,20-tetranor-13,14-didehydro-;
16-(m-trifluoromethyl phenyl)-17,18,19,Z0-tetranor-13,14-
didehydro-;
16-(m-chlorophenyl)-17,18,19,20-tetranor-13,14-didehydro-;
16-(p-fluorophenyl)-17,18,19,20-tetranor-13914-didehydro-;
16-phenyl-18,19S20-trinor-i3,14-didehydro-;
15-methyl-16-phenyl-18,19,20-trinor-13,14-didehydro-;
16-methyl-16-phenyl-18,19,20-trinor-13,14-didehydro ;
15,16-dimethyl-16-phenyl-18,19,20-trinor-13,14-didehydro-;
16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-;
~ L ~ ~ ~ 3704/3803/3823/3833/3879/3893
-100-
15-methyl-16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-
didehydro-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-didehydro-;
16-(p-~luorophenoxy~-17,18,19,20-tetranor-13,14-didehydro-;
16-phenoxy-18,19,20-trinor-13,14-didehydro-;
15-methyl-16 phenoxy-18,19,20-trinor-13,14-didehydro-;
16-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-;
15,16-dimethyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-;
13,14-dihydro-;
15-cyclohexyl-16,17,18,19,20-pentanor-13,14-dihydro-;
17-(2-furyl)-18,19,20-trinor-13,14-dihydro ;
16-(3-thienyl)oxy-17,18,19,20-tetranor-13,14-dihydro-;
17-(3-thienyl)-18,19,20-trinor-13~14-dihydro-;
15-methyl-13,14-dihydro-;
16-methyl-13,14-dihydro-;
15,16-dimethyl-13,14-dihydro-;
16,16-dimethyl-13,14-dihydro-;
17,20-dimethyl-13,14-dihydro-;
16-fluoro-13,14-dihydro-;
15-methyl-16-fluoro-13,14-dihydro-;
16,16-difluoro-13,14-dihydro-;
15-methyl-16,16-difluoro-13,14-dihydro-;
17-phenyl-18,19,20-trinor-13,14-dihydrc-;
Z5 17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-; -
17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;
17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;
15-methyl~17-phenyl-18,19,20-trinor-13,14-dihydro-;
16-methyl-17-phenyl-18919,20-trinor-13,14-dihydro-;
16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;
16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;
16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;
16-phenyl-17,18,19,20-tetranor-13,14-dihydro-;
15-methyl-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-;
15-(m~trifluoromethylphenyl)~17,18319,20-tetranor-13,14-dihydro-;
16-(m-chlorophenyl)-17,18,19,20-tetranor-13,14-dihydro-;
16-(p-fluorophenyl)-17,18,19,20-tetranor-13,14-dihydro--;
16-phenyl-18,19,20-trinor-13,14-dihydro-;
~L2~ 7~ 3704/3803/3823/3833/3879/3893
-101 -
15-methyl-16-phenyl-18919,20-trinor-13,14-dihydro-;
16-methyl-16-phenyl-18,19,20-trinor-13914-dihydro-;
15,16~dimethyl-16-phenyl-18,19,20-trinor-13914-dihydro-;
16 phenoxy-17,18,19,20-~e~ranor-13,14-dihydro-;
15-methyl-16-phenoxy-17,18,19,20-tetranor-13914 dihydro-;
16-(m-trifluorome~hylphenoxy)-17,18j19,20-tetranor-13,14-
dihydro-;
16-(m-chlorophenoxy)-17918,19,20-tetranor-13,14-dihydro-;
16-(p-fluorophenoxy)-17,18,19,20~tetranor-13,14-dihydro-;
16-phenoxy-18,19,20-trinor-13,14~dihydro-;
lS-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;
16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;
15,16-dimethyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;
13-cis-;
15-cyclohexyl-16,17,18,19,20-pentanor-13-cis-;
17-(2-furyl)-18,19,20-trinor-13-cis-;
16-(3-thienyl)oxy-17,18,19,20-tetranor-13-cis-;
17-(3 thienyl)-18,19,20-trinor-13-cis-;
15-methyl-13-cis-;
16-methyl-13-cis-;
15,16-dimethyl-13-cis-;
16,16-dimethyl-13-cis-;
17,20-dimethyl-13-cis-;
16-fluoro-13-cis-;
15-methyl-16-fluoro-13-cis-;
16~16-difluoro-13-cis-;
15-methyl-16,16-difluoro-13-cis-;
17-phenyl-18,19,20 trinor-13-cis ;
17-(m-trifluoromethylphenyl)-18 9 1 9 ~ 20-trinor-13-cis-;
17-(m-chlorophenyl)-18,19,20-trinor-13-cis-;
17-(p-fluorophenyl)-lR,19,20-trinor-13-cis-;
15-methyl-17-phenyl-18,19~20-trinor-13-cis-;
16-methyl-17-phenyl-18,19,20-trinor-13-cis-;
16,16-dimethyl-17-phenyl-18,19~20-trinor-13-cis-;
16-fluoro-17-phenyl-18,19,20-trinor-13-cis-;
16,16-difluoro-17-phenyl-18,19,20-trinor-13-cis-;
16-phenyl-17j18,19,20-tetranor-13-cis-;
15-methyl-16-phenyl-17,18919,20-tetranor-13-cis-;
/3803/3823/3833/3879/3893
-102-
16-(m-trifluoromethylphenyl)-17,18~19,20-tetranor-13-cis-;
16-(m-chlorophenyl)-17,18,19,20-tetranor-13-cis-;
16-(p-fluorophenyl)-17,18,19,20-tetranor-13-cis-;
16-phenyl-18,19,20-trinor-13-cis-;
15-methyl-16-phenyl-18,19,20-trinor-13-cis-;
16-methyl-16~phenyl-18,19,20-trinor-13-cis-;
1$,16-dimethyl-16-phenyl-18,19,20-trinor-13-cis-;
16-phenoxy-17318~19,20-tetranor-13-cis-;
15-methyl-16-phenoxy-17,18,19,20-tetranor-13-cis-;
16 (m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13-cis-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-13-cis-;
16-(p-fluorophenoxy)-17,18,19,20-tetranor-13-cis-;
16-phenoxy-18,19,20-trinor-13-cis-;
15-methyl-16-phenoxy-18,19,20-trinor-13~cis-;
16-methyl-16-phenoxy-18,19,20-trinor-13-cis-j and
15,16-dimethyl-16 phenoxy-18,19,20-trinor-13-cis .
~0
o~ ~
103_ 3704/3803/3823/3833/3879/3893
FORMULAS
COOH
,~
0~
/~
Hd OH
COOH
~4
~a~ ~
I I
1~
Hd OH
HO
~ = 1CooH
~,~ I I I
HO OH
æ
- 104- 3704/3803/3823/3833/3879/3893
FORMULAS (continued)
n
R16 ~ (CH2)n
R47 ~ 9 8~ IV
Y1-C - C-R~
R13 M6 L
R16 ~ (CH2)n
R47 / 9 a~ V
6 ~
~ CH20R32
R
~ Z1-X1
R16 (CH2) n
R17 \ ~ VI
~ CH20R32
R18
CH(R1s)-Zl-X
R16 ~ CH2) n
R17~- t
~ CH2QR32 VII
R13
7i~:
lo~- 3704/3803/3823/3833/3879/3893
FORMULAS ( conti nued )
X 1 -Z4 -o~3
R20~ R23
R21 \ / R VIII
R22~ 24
~_ R33
Rla
HO~
~_ Y1 -C--C-R27
R1~ M6 L1 IX
R 1 5~5l Z 1 - X
R16 ~ (lCHa) n
R17~ X
~_ Y1-C C-R7
Rg M1 L
X1 -Z4 -O -
~/
R20 / ~
R21~a 7~R23 XI
R22~ 8 ~ R24
Go 1~
~ ~DY1-C--C-R7
RE} M1 L 1
- l 06- 3704 /3803 /3823 /3833 /3879 /3893
CHART A
n
oJ~( CH2 ) n
~ XXI
\~Y1 -C--C -R27
R M6 L1
13
1~ 0
V /P(OCH3)2
H0 H
,~C 2
\~ ~, 2)n XXII
--Y1 -C--C-R27
Il 11
t M6 L
Rla
O O
~, (CH2)n-C-CH2-P(OCH3)2
XXIII
~ Y1 -C--C-R2 7
I M6 L
R1a
0 V
~(,CH2) n
XXIV
~Y1 -C~C-R27
Il 11
/ R M6 L 1
1 ~1 \
To XXV To XXVI
7~
- 107- 3704~3803/3823/3~33/3879/3893
CHART A ( c ont i n ued )
From XXIV
R16~ (CH2)n
R37 ~ XXV
~Y1 -C - C-R2,
Il n
R M6 L
1a
\
\ O
(cH2Jn
H2C ~ XXV I
~Y1-C C-R2,
.. Il u
R18 M6 L
o
TsO ~( CH2) n
H2C ~ XXVII
~Y1 -C - C-R27
30I M6 L
R1s
~z~
-108- 3704/3803/38Z3/3833/3879/3893
CHART B
o
Rl6 ~ (cH2)n
R37 ~ XXXI
/ ~ Y1-C - C-R27
Il 11
R18 M6 L
0
LiOC~CH-Z2-CH20R28 XXXII
V Li
HO ~ C~l-Z2-CH20R2~
R16 ~ (~cH2)n XXXIII
R37 ~
~ Y1-C - C-R27
R1a M6 L
\/ V
To To
XXXVI XXXIV
- 109- 3704/3803 /3~23/3833/3879/3~393
CHART B ( cont i nued )
From From
XXX I XXX I I I
z~-CH20R28
, _
R16 ~(,CH2) n
R37~ XXXIV
~Y1 -C - C-R27
I M6 L
R1s
\ /
~ ~Z2-CH20H
R16 ~ (~CH2)n XXXV
R37 ~
~Y1 -C - C-R27
R M6 L1
1a
V
_Z~,.--X1
R16 ~(,CH2) n
R37~ ~ XXXVI
~Y1 -C - C- R7
Il 11
I M1 L
R8
-110- 3704/3803/3823/3833/387g/3893
CHART C
~ (CH2)9-COOH XLI
COOH
CH2)9-CH20H
~ CH20H XLI I
~ (cH2)9-cH2oR28 XLIII
CH20H
(~;3(CH2)9-cH2-oR28 XLIV
CHO
~ 3704/3803/38Z3/3833/3879/3893
CHART D
R~6 ~(cH2)n
R17~ LI
~Y1 -C--~C-R27
Il 11
R M6 L
18
' V
OH
Rl6 4 ,CH2)" LII
R17. ~ ~
~Y1 -C - C-R27
Il !l
R18 M6 L
V
O
O-S-CH3
,~ O
R16 ~ (CH2)n
R \ LIII
17~
~Y1 -C - C-R27
I M6 L
R18
V
To LIV
~ 2
-1 1 2- 37~4/3803/3823/3833/387g/3893
CHART D ( cont i nued )
From L I I I
S \/
S~ ~o2~3
R16 ~CH2)n R16 ~(CH2)n
R17~ ~ LIV ~ R17 7\ ~ LV
~Y1--C C--R27 ~Y1-C C--R27
R1 8 M6 L1 R1 s M6 L
~/
~OAc (CH2)9~CH20R28
~SO2 ,_,CH
R16 ~ (,cH2)n
R1 7~ LV I
Y~Y1 -C~C-R27
Il 11
M6 L
R18
~
~ ( Cl 12) 9-CH20R28
Rl 6 ( CH2 ) n LV I I
Y1-C--C-R27
Il 11
R M6 L~
18
V
To LVIII
o ~
~2~J~'7~2
-113- 3704/3803/3823/3833/3879/3893
CHART D (continued)
From LVII
V
~ ~ (CH2)9-CH20H
R16 ,CH2)n LVIII
R1 7 ~ ~
~ Y1-C - C-R27
Il 11
Rl 8 M6 L
~ ~ (CH2)g~COOR
R16 CH2)n
Rl7 ~ LIX
~ Yl-C - C-R27
Il . Il
R M6 L1
18
(CH2)9-X1
R16 (lc~l2)n LX
R17 ~
~ Y1-C - C-R7
R8 M1~ 1
114 3704/3803/3823/3833/3879/3893
CHART E
(CH2)n
LXI
CH20R31
R3a
V
n
R16 ~ (CH2~n
R1~ ~ ~ LXII
CH20R
R38
Z1 -X1
Rl 6 ~ (/CH2)n
R,7 ~ LXIII
~ CH20R
R
3~
~lZ~
- 115- 3704/3803/3823/3833/387~/3893
CHART F
~f Zl-Xl
R16--~ (,CH2) n
R1, \ ~ LXXI
~--CH20R
R38
\/
D~Z1 -X1
Rl6--~,CH2)n
Rl7t~ LXXII
~CH20H
R38
,~
\/
Z 1 -X1
Rl 6 ~(,CH2 ) n
Rl 7--~ LXX I I I
Y -C ~C-R7
11 11
R8Ml L
1~
-116 3704/3803/3823/3833/3~79/~893
CHART G
R,~ ~ (,CH2)n
R37 ~
LXXXI
Yl-C - C-R27
n I M6 Ll
~18
~ .
Br ~3 ~ ~
P = CH-Z~-COOH
\~==;/ I LXXXII
~/ ~
V
~Z2 -COOH
Rl 6 ~ (,CH2)n
R37 ~ LXXXIII
/ ~ ~ Y1-C - C-R27
R1s M6 L~
- 7 ~ -COOCH~
R16 ~ (CH2)n
R37 ~ LXXXIV
Yl-C - C-R27
Il 11
I M6 L
V R18
To \/
and LXXXIV To LXXXV
-117- 370~/3803/3823/3833/3879/3893
CHART G (continued)
From LXXXIV
V,~ Z2-CH20H
Rl6 ~ (CH2)n
R37 ~ LXXXV
~ ~
~Y1 -C~C-R27
Il 11
I M6 L
R1a
~ ~
HOH2C-Za , H H~ , Z2-CH20H
Rl6 ~(CH2)n R16 ~(CH2)n
R37~ LXXXVI ~31 ~ LXXXVII
~Y1-C ~C - R27 ~Y1-C C - R27
Il ll 11 11
R M6 L1 I M6 L
1~ R
\/ \/
X1~Za H H Z2 - X1
R1~ ~(CH2)n R16 ~ (CH2)n
R17 ~ LXXXVIII R~ ~ LXXXIX
R ~ Y1-C -C - R7 R~ Y1 -C~C-R7
7~l~
~ 3704/3803/3823/3~33/3879/3893
CHART H
o
~ S - CH2-CH2-Z2-CH20R10
5~ H3CN XCI
\~
0
---CH(F)-CH2~Z2^CH20~10 XCII
~ H3CN
R16 ~ (,CH7)n
R17 ~ - ~ XCIII
V ~ Y1-C C-R27
20~ Z2-CH20R1O ~ Rl8 M6 L
R16 (,CH2)n
R17 ~ XCIV
Y1-C - C-R27
Il 11
Rl6 M6 L
~l
F ~ Z2-CH20H
~ ~
R16 ~ (,CH2)n
R~7 t ~ XCV
Y1-C - C-R7
Il 11
R 8 M 1 L
V
To XCVI
-119- 370~/3803/3823/3833/387g/3~93
CHART H (contirlued)
From XCV
F~ ~Z2-COOH
R,6 _~(CH2)n
R17~ XCVI
~Yl -C--C-R7
Il 11
R8 ~1 L1
V
~ r Z2-X1
R16 ~(CH2)n
R17 t( XCVII
~,~Y1-C--C-R7
R,3 M1 L
~2t~
-120~ 3704/3803/3823/3833/3879/3893
CHART I
n
R16 ~(cH2)n
R17 ~ CI
CH20R3
R38
\/
F~Z2-X1
R16_~ (CH2)n
R177~( CII
~~ CH20R
R33
\/
F~ ~ Z2-Xl
R16 ~ (CH2)n
R17 ~ CIII
~Y1 -C - C-R~
Il 11
R8 M1 L
-- 3L~ L'7 ~ ~
-121- 3704t3803/3823/3833/3879/3893
CHART J
R1s ~ CH2-cH2cH
R16 ~ (CHa)n
R17 ~ CXI
~ Y1-C - C-R7
Il 11
R M1 L1
V PhS~
R1~_ ,cH2-cH2-cH-cooR1
R16 ~ (~CHa)n CXII
R17 ~
Y1-C - C-R7
Il 11
R M1 L
H ~ C C --COOR
~ r CH2 ~ H
R16 ~ (C~-la)n CXIII
R17 ~ ( -
Y1-C C-R7
Il 11
R M1 L
~ H ,-X
R~5~ ~ CHa H
R16 ~ ~CH2)n
R17 ~ CXIV
Y1-C C-R7
Il 11
R8 M1 L
7~
-122- 3704/3803/3823/3833/3879/3893
CHART K
R1s~_ ~cH2-cH2-cH2-cooR1
R16 ~ (CH2)n CXXI
R17
CH20R
R38
\/ PhS~
R1~_~ rCH2-CH2-CH-COOR1
R16 ~((,CH2)n CXXII
R17~
CH20R
R
38
V H ~ C C ~ CooR~
R1s~_~ fCH2 H
R16 ~ (,CH2) n CXXI I I
3~ R
CH20R
R33
.7
712
-123- 3704/3803/3823/3833/3879/3893
CHART L
PhSe
R15 CH2~CH2-CH-COOR
~
R16 ~ (/CH2)n
Rl7 ~ CXXXI
CH20R
R
38v
PhSe
CH(R15)-CH2-CH2-CH-COOR
R16 ~ CH~)n
R17 ~ CXXXII
CH20R
R3s
\/ H ~ C C ,~COOR
~ CH(R1 5 ) - CH2 ~ H
R16 ~ (,CH2)n
R,7 ~ CXXXIII
CH20R
38
V ~C=C~
~ CH(R15)-CH2 ~ H
Rl6 ~ (~CH2)n
R17 ~ CXXXIV
~ CH20R
R38
-124- 3704/3803/3823/3833/3879/~893
CHART M
R1 ~ Z3-X1
Rl6 ~ (C~2)n CXLI
R17
~CH20
R3s
V
ScH (R15 ) -Z3-X1
R1 6 ~( CH2) n CXLI I
R~
CH~OR
R3a
'7~
-125-3704/3~03/3823/3833/3879/3893
CHART N
C(R1 5)--Z1--X1
Il
R16 ~cH2)n CLI
R17t--(~
\~ CH20R3
R3
l-:H(~ 7 .-X~
Rl6 ~(cH2)n
R17~ CLII
\r/~Y1-C C-R7
R a M 1 L 1
- 126- 370~/3~03/3823/3833/3879/3893
CHART 0
R1 ~Z1-X
~
K16 ~ (CH2)n
R17. \ ( CLXI
~Y1 -C - C-R7
Il 11
Ra M1 L
\/
CH (R1 s ) - Z1 -X1
R16 ~(,CH2) n CLXI I
R17~
~Y1 -C - C-R7
Il 11
R8 M1 L1
7~2 __
- l 27-3704/3803/3823 j3833/3879/3893
CHART P
~OR2~ CLXXI
Y 1 -C~C -R27
R1 8
M6 L
CH2
~R29 CLXXII
R Y1-C - C-R27
18ll 11
M6 L
' V
CH20H
OR2a CLXXI I I
'Y 1 -C - C -R27
R1 ~ l
M6 L
To CLXXIV
-128- 3704/3803/3823/3$33/387g/3893
CHhRT P (continued)
From CLXXIII
V
CH2OSO2CH3
OR2~ CLXXIV
/Y1-C ~ C-R27
R1 8
M6 L1
HO
CH2OSO2CH3 ,--
~ ~ ~ ~ CLXXV.
~ ~ CLXXV ~ ~
'~Y1-C - C-R27 Rl8Y1 C - C-R27
M6 Ll M6 L
O-Z4- Xl
\ O-Z4-COOR
,~ CLXXVIII ,~
~ ~ ~ J CLXXVXI
R Yl-C - C-R7
~ Yl-C - C-R27
Ml Ll R1 R
M6 L
~t7~
~' -129 3704/3803/3823/3833/3~79/3893
CHART Q
OR28 C ~ CLXXXII
R18Y1-C - G Rz7 > R1aY1-C - C-R27
M6 L1 M6 L
1~
H0 V
H0~ CH0 ~ CLXXXIII
1 -C--~ -R27
R18 y1-C - C~R27 R1~ M6 L
M6 L
V
R100C -Z4 -O
HO ~
J CLXXXV
' Y~-C C-R27
R~ M6 L1
\
\
\
\~
V
To CLXXXVI To CLXXXVIII
~2C~ 2
-130- 3704/3803/3823/3833/3879/3893
CHART Q (continued)
From CLXXXV
1/ \\
~, _~
R102C-Z4-0 R100C-Z~-0
' ~ CLXXXvI ~ CLxxXV
Y~-C ~ C-R27 R1s Y1-lC - ICl-R27
M6 L1 M6 L
V
\/
O--Z4--X1
20 ~ LXXXVII ~ CLXXXIX
R8 Y1-C ~ C-R7 ~ Y1-C -- C-R7
M1 L1 R8 ll
M1 L
O-ZLI -X1
~ ~
Il ~ CXC
~I
R ~ Y1-C ~ C-R7
8 ll ll
M1 L1
-131- 3704/3803/3823/3833/3879/3893
CHART R
C~O
~C - C -R,, CXC I
R 1 s
M6 L
CHO \/
~OR~8 CXCI I
R 1 a ll ll
M6 L
CH20H V
~OR2B
/ Yl -C - C-R27 CXCI I I
R 18
M~ L
X l -z4- V
~,1 CXCIV
~
Rs Y-C -C-R7
M1 L1
~2~.t7~
-132- 3704/3803/3823/3833/3879/3893
CHART S
R28 CCI
~18CH20R3
V
X1--Z4--O
R21 ~
R22 ~ ~ZR23 CCII
R8 ~ H20R3
2n V
X1--Z4--~ .
R21 ~ ~
R22. ~ ~ R23 CCIII
~ / R24
R3 Yl-C - C-R7
Ml L
-133- 3704/3803/3823/3~33/3879/3893
CHART T
CHO
~OH
' Yl-C - C-R27 CCXI
R 1 a
M~ L
~ CCX I I
R 18 Y 1 -C--C -R27
Il 11
M~ L.
X 1 -Z~--
, CCXIII
Rs Y 1 -C - C-R7
M1 L
7~;~
-134- 370~/3803/3823/3833/3879/3893
CHART U
X 1--Z4--
R2 ~
R22 ~ _ R23
~ ~ R24 CCXXI
Rl ~ C=C ,,H
H ~' - C - C-R7
M6 L
Xl-Z4-0
R20
R21 ~
R2 ~ ~ R23 CCXXII
~ R24
~
Rl 8 ~CH0
X1-Z4-0
R21 ~
R22 ~ R23 CCXXIII
~ ~G~R24
~
~`8 ~Y 1 ~C - C-R7
Il 11
Ml L
